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Report of the Translational Research Working Group of the National Cancer Advisory Board
June 2007
Transforming Translation—Harnessing Discovery for Patient and Public BenefitN
atio
nal C
ance
r Ins
titut
e
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
ii Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group
Proposed TRWG Initiatives
Coordinated Management
A1 EstablishacoordinatedNCI-wideorganizationalapproachtomanagethediverseearlytranslationalresearchportfolio,reducefragmentationandredundancy,andensurethatresourcesarefocusedonthemostimportantandpromisingopportunities.
A2 DesignateaspecificportionoftheNCIbudgetforearlytranslationalresearchtofacilitatecoordinatedmanagement,long-termplanning,andprioritizationamongopportunitiesandapproachesaswellastodemonstrateNCI’scommitmenttotranslationalresearch.
A3 Developasetofawardcodesthataccuratelycapturesthenatureandscopeoftheearlytranslationalresearchportfoliotoenableacomplete,sharedunderstandingofNCI’stotalinvestment,helpidentifygapsandopportunities,anddemonstratetheextentoftranslationalactivitytothepublic.
A4 Createatransparent,inclusiveprioritizationprocesstoidentifythemostpromisingearlytranslationalresearchopportunitiesbasedonscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimpact.
Tailored Funding Programs
B1 Modifyguidelinesformultiprojectcollaborativeearlytranslationalresearchawardstofocusresearchonadvancingspecificopportunitiesalongadevelopmentalpathwaytowardpatientbenefit,andtorewardcollaborativeteamscience.
B2 Improveprocessesandmechanismsforreviewandfundingofinvestigator-initiatedearlytranslationalresearchtoincentivizeresearcherstoproposesuchstudies.
B3 Establishaspecialfundingprogramtoadvanceaselectnumberofespeciallypromisingearlytranslationalresearchopportunitiesidentifiedthroughthenewlycreatedprioritizationprocess.
B4 EstablishaprogramforjointNCI/industryfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementarystrengthsofbothpartiestopursueopportunitiesthataremoreattractiveasacombinedeffort.
B5 IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithhigh-priority,milestone-drivenearlytranslationalresearchprojectstobetteraddressthisoftenrate-limitingstepinmovingaproductforwardtoearlyhumantesting.
Operational Effectiveness
C1BuildaprojectmanagementsysteminvolvingstaffbothatNCIandatextramuralinstitutionstofacilitatecoordination,communication,resourceidentificationandaccess,andmanagementofmilestone-basedprogressformultidisciplinary,earlytranslationalresearchprojects.
C2Coordinatecoreservicesessentialforearlytranslationalresearchtoreduceduplicationandensurethathigh-qualityservicesarereadilyaccessibletoallprojectsandinvestigators.
C3 Improvestandardization,qualitycontrolandaccessibilityofannotatedbiospecimenrepositoriesandtheirassociatedanalyticmethodstostrengthenthiskeytranslationalresource.
C4Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccesstopromotecollaborationsamongindustry,academia,NCI,andfoundations.
C5 IncreaseNCIinteractionandcollaborationwithfoundationsandadvocacygroupstocapitalizeupontheircomplementaryskillsandresourcesforadvancingearlytranslationalresearch.
C6Enhancetrainingprogramsandcareerincentivestodevelopandmaintainacommittedearlytranslationalresearchworkforce.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit iii
Report of the NCAB Translational Research Working Group
Initiatives FY08 FY09 FY10 FY11 FY12
A1: Integrated NCI Management
A2: Budget Designation
A3: Translational Research Coding
A4: Prioritization Process
B1: Modify Translational Research Award Guidelines
B2: Improve Investigator-Initiated Translational Research Awards
B3: STRAP Awards
B4: Academia/Industry Collaboration Awards
B5: Develop Integrated Services
C1: Project Management
C2: Core Services Coordination
C3: Enhance Biorepositories
C4: Improve Intellectual Property Negotiations
C5: Enhance Foundation/Advisory Group Collaborations
C6: Enhance Training Programs and Career Incentives
Evaluation
Initiatives FY08 FY09 FY10 FY11 FY12
A1: Integrated NCI Management $800K $800K $850K $850K $850K
A2: Budget Designation — — — — —
A3: Translational Research Coding $150K $150K $150K $150K
A4: Prioritization Process $950K $750K $750K $750K $750K
B1: Modify Translational Research Award Guidelines — — — — —
B2: Improve Investigator-Initiated Translational Research Awards
— — — — —
B3: Special Translational Research Acceleration Project (STRAP) Awards
— — $10M $20M $30M
B4: Academia/Industry Collaboration Awards $5M $10M
B5: Develop Integrated Services — — — — —
C1: Project Management $1.35M $1.3M $1.55M $1.75M $2M
C2: Core Services Coordination $200K $370K — — —
C3: Enhance Biorepositories — — — — —
C4: Improve Intellectual Property Negotiations $100K $530K
C5: Enhance Foundation/Advisory Group Collaborations
— — — — —
C6: Enhance Training Programs and Career Incentives $300K $100K — — —
Evaluation $350K — $350K — $350K
TOTAL $4.05M $3.99M $13.65M $28.5M $44.1M
TRWG Initiatives Summary Timeline
TRWG Initiatives Summary Budget
iv Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group
AcknowledgmentsInadditiontoallofthededicatedmembersoftheTranslationalResearchWorkingGroup,severalotherindividualshaveplayedimportantrolesfacilitatingtheeffortsoftheTRWG,fromitsinceptionthroughthedevelopmentofthisreport.
Lisa Stevens,Ph.D.,Chief,SciencePlanningBranch,andJennifer Kwok,PublicHealthAnalyst,OfficeofScience,PlanningandAssessment,NCI,providedguidanceandsupporttotheTRWGleadershipandwerecriticaltotheoperationandorganizationofTRWGactivities.
Jaye Viner,M.D.,M.P.H.,DeputyDirector,OfficeofCenters,Training,andResources,NCI,providedguidanceanddirectiontotheTRWGleadership.
NOVAResearchCompany:NOVAprovidedoverallsupportfortheTRWGmeetings,Website,materialsproduction,andwriting/notetaking.Dana Young,J.D.,monitoredNOVAsupportactivitiesandcoordinatedsciencewritingforplenaryandworkgroupsessions.Janet BraunprovidedexceptionalplanningandlogisticalsupportforthemanyTRWGmeetings.Ray ButlerandVictor Linprovidedfirst-rateaudiovisualsupportandkeptthingsrunningsmoothlyduringnumerousTRWGmeetings.Michelle Murrayprovidedbackupandonsitemeetingsupport.Erin Milliken,Ph.D.,andKerri Lowrey,J.D.,M.P.H.,providedmanyexcellentpagesofmeetingsummariesandactionitemsthatkeptusontrack.Sue Bentleyprovidedproofreadingandcopyediting.Ed Rorie,M.S.L.S.,providedconsultationontheformattingandfinalprintingofthereport.Dan Eckstein,M.A.,providedprofessionalfacilitation,andAllyson Harkey;ErinMilliken,Ph.D.;Olivia Propst,M.Ed.;Kathy Sedgwick;Melanie Simpson,Ph.D.;Ann Welch,Ph.D.;Dana Young,J.D.;andAllison Zambon,M.H.S.,providedexcellentsciencewritingsupport.
ScienceApplicationsInternationalCorporation(SAIC):Jeffrey Zalatoris,Ph.D.,providedcoordinationofSAIC’sPortfolioAnalysiswork,withassistancefromGregory Cole,Ph.D.,Karen Rulli,Ph.D.,Adeyinka Smith,M.S.,Quentin Scott,Ph.D.,Allart Kok,M.S.,andJoshua Wolfe,Ph.D.Kathy Sorrow,M.S.,Deborah Berlyne,Ph.D.,Julie Ter Borg,M.P.H.,andAdam Book,Ph.D.providedinvaluablesciencewritingsupport.
Gary Dorfman,M.D.,SpecialAssistanttotheAssociateDirectorforImageGuidedInterventionsintheDivisionofCancerTreatmentandDiagnosis,NCI,ablyrepresentedtheCancerImagingProgram,providingcriticalinputandmanyhourstotheInterventiveDeviceandImaging-relatedRiskAssessmentDevicepathways.
Henry Rodriguez,Ph.D.,M.B.A.,ablyrepresentedtheOfficeofTechnologyandIndustrialRelationsoftheNCIintheTRWGdeliberations.
Jane Reese-Coulbourne,M.S.,M.B.A.,providedvaluableinputfromtheadvocateperspectiveintothepenultimateTRWGreport.
David Dilts,Ph.D.,M.B.A.,ProfessorofEngineeringManagementandManagementatVanderbiltUniversity,passedoninsightsfromthebusinessworldintohowthebarrierstotranslationalresearchmightbeaddressed.
Vanessa Hill,DepartmentofCancerBiologyatVanderbiltUniversity,providedcriticalsupportinassistingtheco-chairinmanagingTRWGactivities.
ScienceandTechnologyPolicyInstitute(STPI)oftheInstituteforDefenseAnalyses:ThecontributionsoftheSTPIteamtothedevelopmentandexecutionoftheTRWGreportcannotbeoverestimated.EachmemberoftheSTPIteam,Oren Grad,M.D.,Ph.D.,Brian Zuckerman,Ph.D.,Maureen McArthur,andAlexis WilsonplayedanessentialroleinmovingallphasesofTRWGactivitiesforwardinaneffectiveandinclusivemanner,andinparticularweacknowledgethecontributionsofDr.GradtothePathwaydiagramsandDr.ZuckermantotheProcessAnalysis.Judith Hautala,Ph.D.,servedasLeadCoordinatoroftheSTPIteamandwasexemplaryinherservicetotheTRWGeffort.Shespentcountlesshoursorganizingandcoordinatingtheteam’sinteractions,andmovingustowardthedevelopmentoffinalrecommendationsandimplementationstrategies.WearedeeplygratefulfortheSTPIteam’smanycontributions.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit v
Report of the NCAB Translational Research Working Group—Members of the TRWG
Chair
Ernest T. Hawk, M.D., M.P.H.Director,OfficeofCenters,Training,andResourcesOfficeoftheDirectorNationalCancerInstituteBethesda,MD
Co-Chairs
Lynn M. Matrisian, Ph.D.ProfessorandChair,DepartmentofCancerBiologyVanderbiltUniversityNashville,TN
William G. Nelson, M.D., Ph.D.Professor,Oncology,Urology,Pharmacology,Medicine,andPathologySidneyKimmelComprehensiveCancerCenteratJohnsHopkinsBaltimore,MD
Members
James L. Abbruzzese, M.D., F.A.C.P.Professor/Chairman,DivisionofCancerMedicineTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX
David S. Alberts, M.D.Director,ArizonaCancerCenterUniversityofArizonaTucson,AZ
Kenneth C. Anderson, M.D.KraftFamilyProfessorofMedicineDivisionofHematologicNeoplasiaHarvardMedicalSchoolBoston,MA
Robert C. Bast, M.D.VicePresident,TranslationalResearchTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX
Darell D. Bigner, M.D., Ph.D.JonesCancerResearchProfessorDeputyDirector,DukeComprehensiveCancerCenterDurham,NC
Kenneth H. Buetow, Ph.D.AssociateDirector,BioinformaticsandInformationTechnologyNationalCancerInstituteBethesda,MD
Translational Research Working Group
vi Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Members of the TRWG
Michael A. Caligiuri, M.D.Director,ComprehensiveCancerCenterTheOhioStateUniversityColumbus,OH
Mac Cheever, M.D.DirectorofSolidTumorResearchFredHutchinsonCancerResearchCenterSeattle,WA
Jerry M. Collins, Ph.D.AssociateDirector,DevelopmentalTherapeuticsDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD
Richard J. Cote, M.D.ProfessorofPathologyandUrology,KeckSchoolofMedicineNorrisComprehensiveCancerCenterUniversityofSouthernCaliforniaLosAngeles,CA
Sara A. Courtneidge, Ph.D.Professor/ProgramDirector,CellAdhesionandExtracellularMatrixProgramBurnhamInstituteforMedicalResearchLaJolla,CA
Kenneth H. Cowan, M.D., Ph.D.Director,EppleyCancerCenterUniversityofNebraskaMedicalCenterOmaha,NE
Phillip A. Dennis, M.D., Ph.D.SeniorInvestigator,MedicalOncologyBranchCenterforCancerResearchNationalCancerInstituteBethesda,MD
Adrian M. Di Bisceglie, M.D., F.A.C.P.ProfessorofInternalMedicine/ChiefofHepatology,DivisionofGastroenterologyandHepatologySt.LouisUniversitySchoolofMedicineSt.Louis,MO
James H. Doroshow, M.D.Director,DivisionofCancerTreatmentandDiagnosisNationalCancerInstituteBethesda,MD
Gregory J. Downing, D.O., Ph.D.Director,OfficeofTechnologyandIndustrialRelationsNationalCancerInstituteBethesda,MD
Transforming Translation—Harnessing Discovery for Patient and Public Benefit vii
Report of the NCAB Translational Research Working Group—Members of the TRWG
Steven M. Dubinett, M.D.ProfessorofMedicineandPathologyDirector,LungCancerResearchProgramJonssonComprehensiveCancerCenterDavidGeffenSchoolofMedicineatUCLALosAngeles,CA
Raymond N. DuBois, M.D., Ph.D.Director,TheVanderbilt-IngramCancerCenterNashville,TN
Peter D. Emanuel, M.D.Professor,DivisionofHematology-OncologyUniversityofAlabamaatBirminghamBirmingham,AL
Laura Esserman, M.D., M.B.A.Director,CarolFrancBuckBreastCareCenterProfessorofSurgeryandRadiologyUniversityofCalifornia,SanFranciscoSanFrancisco,CA
Laurie FentonPresident,LungCancerAllianceWashington,DC
Tona M. Gilmer, Ph.D.Director,U.S.HumanBiomarkerLabsTranslationalMedicineandGeneticsGlaxoSmithKlineResearchTrianglePark,NC
Jorge Gomez, M.D., Ph.D.BranchChief,OrganSystemsBranchNationalCancerInstituteRockville,MD
Gary Gordon, M.D., Ph.D.DivisionalVicePresident,GlobalOncologyDevelopmentGlobalPharmaceuticalResearchandDevelopmentAbbottLaboratoriesAbbottPark,IL
Joe W. Gray, Ph.D.DivisionDirector,AssociateLaboratoryLifeSciencesDivisionLawrenceBerkeleyNationalLaboratoryBerkeley,CA
Ellen R. Gritz, Ph.D.ProfessorandChair,DepartmentofBehavioralScienceTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX
viii Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Members of the TRWG
William N. Hait, M.D., Ph.D.Director,MedicalOncologyTheCancerInstituteofNewJerseyNewBrunswick,NJ
Waun Ki Hong, M.D.Head/Professor,CancerMedicineTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX
David Kerr, C.B.E., M.D., D.Sc., M.A., F.R.C.P., FMedSciRhodesProfessor,CancerTherapeuticsandClinicalPharmacologyHead,DepartmentofClinicalPharmacologyDirector,NationalTranslationalCancerResearchNetworkOxford,UnitedKingdom
Theodore S. Lawrence, M.D., Ph.D.ProfessorandChair,DepartmentofRadiationOncologyUniversityofMichiganAnnArbor,MI
Paul J. Limburg, M.D., M.P.H.AssociateProfessorofMedicineDivisionofGastroenterologyandHepatologyMayoClinicCollegeofMedicineRochester,MN
A. Thomas Look, M.D.ViceChairforResearchDepartmentofPediatricOncologyDana-FarberCancerInstituteBoston,MA
Anne E. Lubenow, M.P.H.Chief,CommunicationsProgramandStrategyBranchOfficeofCommunicationsNationalCancerInstituteBethesda,MD
H. Kim Lyerly, M.D.Director,ComprehensiveCancerCenterDukeUniversityDurham,NC
David E. Maslow, Ph.D.Chief,ResourcesandTrainingReviewBranchDivisionofExtramuralActivitiesNationalCancerInstituteRockville,MD
Gail P. McGrathPresident,NationalDirectorofGovernmentAffairsNationalPatientAdvocateFoundationWashington,DC
Transforming Translation—Harnessing Discovery for Patient and Public Benefit ix
Report of the NCAB Translational Research Working Group—Members of the TRWG
Howard McLeod, Pharm.D.FredN.EshelmanDistinguishedProfessorDirector,UNCInstituteforPharmacogenomicsandIndividualizedTherapy,OncologyDivisionUniversityofNorthCarolina,ChapelHillChapelHill,NC
Anne McTiernan, M.D., Ph.D.CancerPreventionFredHutchinsonCancerResearchCenterSeattle,WA
Suresh Mohla, Ph.D.Chief,TumorBiologyandMetastasisBranchDivisionofCancerBiologyNationalCancerInstituteRockville,MD
Ida M. Moore, D.N.Sc., R.N., F.A.A.N.Professor,NursingPracticeDivisionUniversityofArizonaCollegeofNursingTucson,AZ
Cherie Nichols, M.B.A.Director,OfficeofSciencePlanningandAssessmentOfficeoftheDirectorNationalCancerInstituteBethesda,MD
J. Carl Oberholtzer, M.D., Ph.D.AssociateDirectorforTrainingOfficeofCenters,Training,andResourcesOfficeoftheDirectorNationalCancerInstituteBethesda,MD
Funmi Olopade, M.B.B.S., F.A.C.P.Director,FellowshipTrainingProgramDepartmentofHematology/OncologyUniversityofChicagoChicago,IL
Roman Perez-Soler, M.D.Chairman,DepartmentofOncologyMontefioreMedicalCenterAlbertEinsteinCollegeofMedicineBronx,NY
Charles S. Rabkin, M.D.MedicalEpidemiologistViralEpidemiologyBranchDivisionofCancerEpidemiologyandGeneticsNationalCancerInstituteRockville,MD
x Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Members of the TRWG
Brian J. Reid, M.D., Ph.D.Member,HumanBiologyandPublicHealthSciencesFredHutchinsonCancerResearchCenterSeattle,WA
David Scheinberg, M.D., Ph.D.Chair,MolecularPharmacologyandChemistryProgramChair,ExperimentalTherapeuticsCenterMemorialSloan-KetteringCancerCenterNewYork,NY
Richard L. Schilsky, M.D.ProfessorofMedicine/AssociateDeanforClinicalResearchBiologicalSciencesDivisionUniversityofChicagoChicago,IL
Jeffrey Schlom, Ph.D.LabChief,LaboratoryofTumorImmunologyandBiologyCenterforCancerResearchNationalCancerInstituteBethesda,MD
Mitchell D. Schnall, M.D., Ph.D.AssociateChairforResearch,DepartmentofRadiologyUniversityofPennsylvaniaPhiladelphia,PA
Thomas A. Sellers, Ph.D., M.P.H.AssociateCenterDirector,CancerPreventionandControlDivisionH.LeeMoffittCancerCenterandResearchInstituteTampa,FL
David Sidransky, M.D., Ph.D.Director/Professor,HeadandNeckCancerResearchJohnsHopkinsMedicalInstitutionsBaltimore,MD
Ellen V. Sigal, Ph.D.Chairperson,FriendsofCancerResearchArlington,VA
Richard M. Simon, D.Sc.Chief,BiometricResearchBranchDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD
Sudhir Srivastava, Ph.D., M.P.H.Chief,CancerBiomarkersResearchGroupDivisionofCancerPreventionNationalCancerInstituteRockville,MD
Transforming Translation—Harnessing Discovery for Patient and Public Benefit xi
Report of the NCAB Translational Research Working Group—Members of the TRWG
Daniel C. Sullivan, M.D.AssociateDirector,CancerImagingProgramDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD
Thea D. Tlsty, Ph.D.Professor,DepartmentofPathologyUniversityofCalifornia,SanFranciscoSanFrancisco,CA
Louis M. Weiner, M.D.VicePresident,TranslationalResearchMedicalScienceDivisionFoxChaseCancerCenterPhiladelphia,PA
Janet Woodcock, M.D.DeputyCommissionerandChiefMedicalOfficerOfficeoftheCommissionerFoodandDrugAdministrationRockville,MD
This Page Intentionally Left Blank.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit xiii
Report of the NCAB Translational Research Working Group—Table of Contents
Table of Contents
Executive Summary ............................................................................................................................ 1
Summary Vision .................................................................................................................................. 5
Introduction ......................................................................................................................................... 9
Coordinated Management ................................................................................................................ 13
Initiative A1: Establishaflexible,integratedorganizationalapproachthatcoordinatesearlytranslationalresearchacrosstheNationalCancerInstitute...............................................................14
Initiative A2: DesignateaspecificportionoftheNationalCancerInstitutebudgetforearlytranslationalresearch.......................................................................................................23
Initiative A3: Developasetofawardcodesthataccuratelycapturethenatureandscopeoftheearlytranslationalresearchportfolio...............................................................................25
Initiative A4: Establishadistinctiveprioritizationprocessforearlytranslationalresearch..................................................................................................................................28
Tailored Funding Programs .............................................................................................................. 33
Initiative B1: Modifymultiprojectcollaborativeawardguidelines,asappropriate,tofacilitateearlytranslationalresearch......................................................................................................34
Initiative B2: Improveprocessesandmechanismsforfundinginvestigator-initiatedearlytranslationalresearch......................................................................................38
Initiative B3: Establishaspecialtranslationalresearchfundingprogramtoadvanceprioritizedearlytranslationalresearchopportunities................................................40
Initiative B4: Establishafundingprogramforearlytranslationalresearchthatrequiresacademic/industrycollaborationinvolvingresourcesharingand/orco-funding.......................................45
Initiative B5: IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithmilestone-drivenearlytranslationalresearchprojects..............................50
Operational Effectiveness ................................................................................................................. 53
Initiative C1: Establishaformalprojectmanagementsystemforearlytranslationalresearch.......................................54
Initiative C2: Establishasystemtocoordinatecoreservicesessentialforearlytranslationalresearch..........................59
Initiative C3: Enhancequalityandaccessibilityofannotatedbiospecimenrepositoriesandassociatedanalyticmethods.......................................................................................................................64
Initiative C4: Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccess.........................................................................................................................................68
Initiative C5: Enhanceinteractionsandcollaborationswithfoundationsandadvocacygroupstoadvanceearlytranslationalresearch......................................................................................................72
Initiative C6: Enhancetrainingandcareerincentivesforearlytranslationalresearch....................................................75
xiv Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Table of Contents
Timeline and Budget ......................................................................................................................... 79
Evaluation and Outcome Measures ................................................................................................. 91
Appendices ......................................................................................................................................... 95
Appendix A: FoundationalDocuments...........................................................................................................................97
Appendix B: TRWGTranslationalResearchDefinitionandScopeofActivity..............................................................99
Appendix C: TRWGDevelopmentalPathwaystoClinicalGoals................................................................................101
Appendix D: TranslationalResearchPortfoliofortheNCITranslationalResearchWorkingGroup........................... 111
Appendix E: ProcessAnalysisfortheNCITranslationalResearchWorkingGroup....................................................125
Appendix F: TRWGMeetingDates..............................................................................................................................151
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 1
Report of the NCAB Translational Research Working Group—Executive Summary
Executive Summary
InJune2005,theTranslationalResearchWorkingGroup(TRWG)wasestablishedundertheauspicesoftheNationalCancerAdvisoryBoard(NCAB)toadvisetheNationalCancerInstitute(NCI)onthefuturecourseofNCI-supportedtranslationalresearch,acriticallinkinrealizingthepromiseofmolecularoncologyforpatientandpublicbenefit.TheTRWGwasconstitutedasabroadandinclusivepaneloftranslationalresearchexperts,includingacademicscientistsandclinicians,representativesfromindustryandfoundations,patientadvocates,andNCIstaff.
TheTRWGfirstreachedconsensusonanoperationaldefinitionoftranslationalresearchas“researchthattransformsscientificdiscoveriesarisinginthelab,clinic,orpopulationintonewclinicaltoolsandapplicationsthatreducecancerincidence,morbidity,andmortality.”Forthefocusofitsdeliberations,theTRWGfurtherselectedthe“earlytranslationalresearch”portionofthePresident’sCancerPanelTranslationalContinuum,whichissituatedbetweenfundamentaldiscoveryresearchandPhaseIIIclinicaltrials(seeFigure1).TheTRWGthusintentionallydidnotseektochangeanyaspectofdiscoveryresearch—thelargestcomponentoftheNCIextramuralresearchfundingportfolio—andalsofocusedoncomplementingandextending,butnotduplicating,theinitiativesoftheClinicalTrialsWorkingGroup,whichconcentrateditsattentiononclinicaltrials.TheTRWGalsoviewedtheareasofdisseminationandadoption,whilecriticallyimportanttotheoverallsuccessofthecontinuum,tobeoutsidethescopeofitsdeliberations.
TheTRWGnextdraftedsixdevelopmentalpathwaystoclinicalgoals,definingtheoverallcourseofearlytranslationforeachofsixkeydomains—biospecimen-basedriskassessmentdevices,image-basedriskassessmentagents/techniques,agents,immuneresponsemodifiers,interventivedevices,andlifestylealterations.TheTRWGalsoconductedananalysisofNCI’scurrentportfoliointranslationalresearch,whichrevealedawiderangeofactivitiessupportedthroughmanydifferentmechanismsincludingbothinvestigator-initiatedandsolicitedprograms.Inaddition,aprocessanalysisinvolving20recenttranslational“successes”wasconductedtoidentifytheNCIprograms,individuals,organizations,etc.,involvedinachievingtranslationalprogresswithinthecurrentsystem.Finally,inanattempttolearnfromothers’experiencesandrecommendations,theTRWGreviewed11priorreportsandplanningdocumentsrelevanttotranslationalresearchthathadbeengeneratedoverthepreviousseveralyears.
Figure 1. TRWG Scope of Activity: The Translational Continuum*
Basic Science Discovery
Early Translation Late Translation Dissemination Adoption
• Promising molecule or gene target
• Candidate protein biomarker
• Basic epidemiologic finding
• Partnerships and collaboration (academia, government, industry)
• Intervention development
• Phase I/II trials
• Phase III trials• Regulatory approval• Partnerships• Production and
commercialization• Phase IV trials
– approval for additional uses
• Payment mechanism(s) established to support adoption
• Health services research to support dissemination and adoption
(newdrug,assay,device,behavioralintervention,educationalmaterial,training)• To community
health providers• To patients and
public
• Adoption of advance by providers, patients, public
• Payment mechanism(s) in place to enable adoption
TRWG Activity
*FromthePresident’sCancerPanel’s2004-2005reportTranslatingResearchIntoCancerCare:DeliveringonthePromise.
2 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Executive Summary
Inassessingtherationaleforchange,theTRWGrecognizedfromtheoutsetthattheNCI-supportedtranslationalresearchenterpriseisnotkeepingpacewiththeenormousopportunitiespresentedbyadvancesinknowledgeandtechnologyoverthepast40yearsofcancerresearch.Basedontheseopportunities,publicexpectationsforsignificantadvancesincancerprevention,treatment,andcarearerising,yetresourcesdevotedtocancerresearchhavereachedaplateau.Giventhisclimate,theTRWGaskedhowNCIcouldbestensurethatthemostpromisingbasicresearchconceptsenterthedevelopmentalpathwaysandareadvancedrapidlyandefficientlyeithertotranslationalsuccessortoaproductivefailurethatusefullyinformsfurthertranslationalordiscoveryresearch.
Tomeetthischallenge,theTRWGidentifiedfourcriticalobjectivesforanationalearlytranslationalresearchenterprisethatcanadvancediscoveriesmoreeffectivelytowardearlyhumantestingofanewdrug,biologic,diagnostic/screeningtest,orothertherapeutic,diagnostic,orpreventativeintervention.Thefirstobjectivewastoimprovecoordinationandcollaborationandinstillacultureofactive,goal-orientedmanagementforbothindividualprojectsandtheenterpriseasawhole.Thesecondobjectivewastoimproveidentificationofthemostpromisingearlytranslationalresearchopportunitiesacrossalldiseasesites,populations,andpathwaystoclinicalgoalsthroughatransparent,inclusiveprocessinvolvingallrelevantstakeholdersanddrivenby:a)thestrengthofthescientificrationale,b)thetechnicalfeasibilityofthedevelopmentapproach,c)theexpectedclinicalorpublichealthimpact,andd)theriskthattheopportunitywouldnotbetakenforwardbyindustry.Thethirdobjectivewastotailorbothnewandexistingfundingprogramstofacilitateearlytranslationalresearchprogressandincentivizeresearcherparticipation.Thefourthobjectivewastoenhancetheoperationalefficiencyandeffectivenessofearlytranslationalresearchprojectsandthemanysupportingactivitiesessentialtotheenterprise,includingtheparticipationofpatientsandadvocacygroups.
Inaddressingtheseobjectives,theTRWGproceededthroughaconsensus-buildingprocessinvolvingthreesequentialstages.First,theTRWGidentifiedthosespecificaspectsofthecurrentNCI-supportedearlytranslationalresearchenterpriseinneedofimprovement.Thesecondstagewastodeveloprecommendationsfortargetedenhancementsineachofthoseaspects,someofwhichwerepresentedtotheNCABonJune14,2006.Inthethirdstage,theTRWGdefinedspecificinitiativesbasedonthoserecommendationsanddesignedimplementationplansfortheirpracticalrealization.Ineachofthesestages,theTRWGobtainedsubstantiveandvaluableinputfromthebroadercancerresearchcommunitythroughbothInternet-basedpublicforumsandinvitedRoundtableMeetings.
Thistransparent,inclusive,andstrategicallydrivenprocess,involvingallthecriticalstakeholdergroupsinthecancerearlytranslationalresearchcommunity,resultedinthe15initiativesdetailedinthisreporton“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”Theproposedinitiativescoverthefullbreadthofthecurrentandfutureearlytranslationalresearchenterprise,andeachaddressesoneofthecommonthemesderivedfromtheTRWGgoals:CoordinatedManagement,TailoredFundingPrograms,orOperationalEffectiveness.Takentogether,theseinitiativeswillstrengthenandtransformtheNCI-supportedearlytranslationalresearchenterpriseintoanationaleffortthatintegratestheindividuallystrongcomponentsofthecurrentsystemintoacoordinatedandcollaborativeendeavorfocusedonthedistinctiveneedsandcharacteristicsofearlytranslationalresearchandoptimizedforitssuccess.
Theinitiatives,whicharedescribedindetailinthereport,aresummarizedbelow.
Coordinated Management
• EstablishacoordinatedNCI-wideorganizationalapproachtomanagethediverseearlytranslationalresearchportfolio,reducefragmentationandredundancy,andensurethatresourcesarefocusedonthemostimportantandpromisingopportunities.
• DesignateaspecificportionoftheNCIbudgetforearlytranslationalresearchtofacilitatecoordinatedmanagement,long-termplanning,andprioritizationamongopportunitiesandapproachesaswellastodemonstrateNCI’scommitmenttotranslationalresearch.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 3
Report of the NCAB Translational Research Working Group—Executive Summary
• Developasetofawardcodesthataccuratelycapturesthenatureandscopeoftheearlytranslationalresearchportfoliotoenableacomplete,sharedunderstandingofNCI’stotalinvestment,helpidentifygapsandopportunities,anddemonstratetheextentoftranslationalactivitytothepublic.
• Createatransparent,inclusiveprioritizationprocesstoidentifythemostpromisingearlytranslationalresearchopportunitiesbasedonscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimpact.
Tailored Funding Programs
• Modifyguidelinesformultiproject,collaborativeearlytranslationalresearchawardstofocusresearchonadvancingspecificopportunitiesalongadevelopmentalpathwaytowardpatientbenefit,andtorewardcollaborativeteamscience.
• Improveprocessesandmechanismsforreviewandfundingofinvestigator-initiatedearlytranslationalresearchtoincentivizeresearcherstoproposesuchstudies.
• Establishaspecialfundingprogramtoadvanceaselectnumberofespeciallypromisingearlytranslationalresearchopportunitiesidentifiedthroughthenewlycreatedprioritizationprocess.
• EstablishaprogramforjointNCI/industryfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementarystrengthsofbothpartiestopursueopportunitiesthataremoreattractiveasacombinedeffort.
• IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithhigh-priority,milestone-drivenearlytranslationalresearchprojectstobetteraddressthisoftenrate-limitingstepinmovingaproductforwardtoearlyhumantesting.
Operational Effectiveness
• BuildaprojectmanagementsysteminvolvingstaffbothatNCIandatextramuralinstitutionstofacilitatecoordination,communication,resourceidentificationandaccess,andmanagementofmilestone-basedprogressformultidisciplinaryearlytranslationalresearchprojects.
• Coordinatecoreservicesessentialforearlytranslationalresearchtoreduceduplicationandensurethathigh-qualityservicesarereadilyaccessibletoallprojectsandinvestigators.
• Improvestandardization,qualitycontrol,andaccessibilityofannotatedbiospecimenrepositoriesandtheirassociatedanalyticmethodstostrengthenthiskeytranslationalresource.
• Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccesstopromotecollaborationsamongindustry,academia,NCI,andfoundations.
• IncreaseNCIinteractionandcollaborationwithfoundationsandadvocacygroupstocapitalizeupontheircomplementaryskillsandresourcesforadvancingearlytranslationalresearch.
• Enhancetrainingprogramsandcareerincentivestodevelopandmaintainacommittedearlytranslationalresearchworkforce.
Foreachoftheseinitiatives,theTRWGdevelopedanimplementationplantorealizeitsgoals.TheindividualplansweredevelopedthroughmanyhoursofiterativediscussionanddeliberationbytheTRWG,firstwithinthesubcommitteethatgeneratedtheinitiativeandtheninplenarysession.Whilecompleteconsensuswasnotachievedonallspecificpoints,therewaswidespreadsupportforalloftheproposedplans.Theplanspresentedinthereportthusrepresentthecombinedwisdomofthe62TRWGmembersconcerninghoweachoftheinitiativesmightbeimplementedinaneffectiveandinnovative,yetfeasible,manner.ThegoalwastodevelopimplementationplansthatwouldbuildonthebestofthecurrentNCIearlytranslationalresearchsystemwhileproposingspecificnewactionstepsdesignedtoachievetheimprovements
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Report of the NCAB Translational Research Working Group—Executive Summary
envisionedbytheinitiatives.TheTRWGrecognizesthatactualimplementationmaywellproceedalongadifferentcourse.TheplansdetailedinthereportareofferedasanapproachwhichtheTRWGbelievescouldachievethegoalsoftheproposedinitiatives.
Theimplementationplanproposedforeachinitiativeincludesanassociatedtimelineandbudget.TheTRWGestimatesthatimplementationofalltheinitiatives,accordingtotheproposedplans,wouldrequire4to5yearstocomplete,withthefullimpactonroutineNCIoperationalpracticesexpectedtorequireatleast2to3additionalyears.Inthistimeline,allinitiativesaretargetedtobeginimplementationbytheendofyearthree.TheimplementationeffortasoutlinedisprojectedbytheTRWGtocost$94Mover5years.Estimatedexpensesincreasefromapproximately$4MeachinFY08andFY09to$13.5MinFY10,$28.5MinFY11,and$44MinFY12.TheincreasedexpendituresinFY10-12aredueentirelytodirectsupportfortheextramuralcommunityassociatedwiththenewtailoredearlytranslationalresearchfundingprograms.Oftheannual$4Minnonextramuralfunding,50%istooperatetheprojectmanagementsystem,25%istosupporttheprioritizationprocess,and25%isfortheNCImanagementandadministrativestructurenecessarytoimplementtheremaininginitiativesandeffectivelyguidethetransformedenterprise.
Majorchangesinanongoingenterprise,suchastheTRWGproposesforNCI-supportedearlytranslationalresearch,shouldbeundertakenonlyifthereisaplantoevaluatethesuccessofthosechanges.Therefore,iftheinitiativesareimplemented,theTRWGproposesthataformalevaluationsystembeestablishedtodeterminetheimpactoftheinitiatives.Theproposedevaluationsystemwouldincludemeasuresthataddressthreeimportantdimensionsofsuccess.Thefirstareprogrammanagementmeasurestoevaluatetheeffectivenesswithwhichtheinitiativesareimplemented.Thesecondaresystemperformancemeasurestodeterminewhetherthenewstructures,processes,andprogramsareachievingtheobjectivesofamorecoordinated,collaborative,transparent,efficient,andgoal-orientedearlytranslationalresearchenterprisethatisbettermanagedandprioritized.Thethirdaresystemoutcomemeasurestoassesswhetherthecombinedchangesresultinadvancinganincreasednumberofearlytranslationalresearchopportunitiestomiddle-andlate-stagehumanstudies.
ImplementationoftheTRWGinitiatives,whetherasoutlinedinthereportorbyothermeans,willrequireconsiderableadditionaleffortbythecancertranslationalresearchcommunity,aswellasafocused,butmodest,financialinvestmentbyNCI.TheTRWGbelievesthatthiscommitmentandinvestmentareessentialtoensurethatthemuchlargerongoingnationalinvestmentinearlytranslationalresearchisappropriatelymanagedandtargetedtohelprealizethepromiseofmolecularoncologybymovingimportantnewdiscoverieseffectivelytowardearlyhumantesting.Byembracingtheseinitiatives,NCIandthecancerresearchcommunitywilldemonstratetheirstrongcommitmenttoharnessingtheadvancesincancerbiologyachievedthroughthelast40yearsofprogressforpatientandpublicbenefit.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 5
Report of the NCAB Translational Research Working Group—Summary Vision
Summary Vision
Build a focused, collaborative, multidisciplinary enterprise, tailored to the distinctive requirements of early translational research, which transforms and
strengthens this essential link from discovery to patient and public benefit.
Advancesinunderstandingthemolecularandcellulareventsunderlyingcancerofferanunprecedentedopportunitytotranslatediscoveriesintotangiblebenefitsforpatientsandthepublic.However,developmentoftargeted,molecularapproachestotherapy,prevention,prediction,detection,diagnosis,andprognosisrequiresnotonlyaneffectiveclinicaltrialssystembutalsoadynamicearlytranslationalresearchenterprisethatcantransformfundamentaldiscoveriesfromthelab,clinic,orpopulationintospecificproducts,interventions,orlifestylealterationsreadyforhumantesting.
Inparticular,earlytranslationalresearchhasenormouspotentialtoimprovetheoutcomeofclinicaltrialsdirectedatnewtherapiesbybothestablishingreliablemolecularmarkersoftherapeuticresponseandclearlyidentifyingthepatientsmostlikelytorespondbasedonthemolecularcharacteristicsoftheirdisease.Clinicaltrialsinformedbysuchmolecularunderstandingwillbemoreefficientandputfewerpatientsatriskthantheempiricapproachesusedinthepast.
Earlytranslationalresearchposesthreeprimarychallenges.Thefirstistoensurethatthemostpromisingandimportantdiscoveriesareidentifiedandmovedforwardintodevelopment.Thesecondistoensurethatthesediscoveriesadvancethroughthecomplex,multidisciplinary,goal-orienteddevelopmentprocessasefficientlyandeffectivelyaspossible.Thethirdistoensureasmooth,timelytransitionbetweenearlytranslationalresearchandlate-stagehumantrials,productcommercialization,andcommunitydissemination.
Meetingthesechallengeswillrequireacoordinatedandcollaborativenationalenterprisefocusedonthedistinctiveneedsandcharacteristicsofearlytranslationalresearchandoptimizedforitsconduct.Suchanenterpriseisneededbecausetranslationalresearchhasonlyrecentlyemergedasafocusedendeavor,distinctfromdiscoveryorclinicalresearch,dueatleastinparttotheenormousarrayofdiscoveriesonwhichscientificallydrivendevelopmentofabroadrangeofnewcancerinterventionscanbebased.ThisenterprisewillalsoimprovetheNationalCancerInstitute’s(NCI)abilitytoensurethatallAmericansbenefitfromtheNation’sinvestmentincancerresearch.Thisincludespatientsafflictedwithrarecancers,whichmaynotbeattractivetargetsforindustry-supportedearly-stagedevelopment,andpopulationsthataredisproportionatelyaffectedbycertaincancersorunderservedbycurrentapproachestoresearch,prevention,andtreatment.
BuildingamoreeffectiveandcoordinatedNCIearlytranslationalresearchenterprisewillrequireashareddefinitionofwhatconstitutesearlytranslationalresearch,anaccurateandcomprehensiveunderstandingofthescopeofongoingactivity,andacommitmenttoadequatefunding.GiventhatearlytranslationalresearchisdistributedacrossvirtuallyallNCIDivisions,Centers,andOffices,anintegrated,cross-NCIapproachisneededtoadequatelyanalyzetheportfolioofcurrentawardsandaddressanyidentifiedgaps,overlaps,orinefficienciesinallocationofresources.Acomprehensive,coordinatedapproachisalsorequiredtoensurethatscarceresourcesareequitablybalancedacrossdiseasesites,affectedpopulations,andthedevelopmentalpathwaystoclinicalgoals,andarefocusedonprojectswiththegreatestpotentialforbothtranslationalsuccessandimpactonpatientsandthepublic.
Theaccumulatingnumberofearlytranslationalresearchopportunities,coupledwithfiniteresources,requiresatransparent,inclusive,andfact-basedprocessforidentifyingthoseopportunitiesthataremostpromisingfordevelopment.Scientificquality,thegoldstandardfordiscoveryresearch,isanessentialcriterionforsuchaprocess.However,earlytranslationalresearchmustalsobejudgedbythetechnicalfeasibilityofafocuseddevelopmenteffort,thepotentialimpactonacriticalunmetclinicalorpublichealthneed,andthelikelihoodthattheopportunitywillnotbetakenforwardbyprivateindustrywithoutNCIinvolvement.Onceacomprehensiveandinclusiveprocesstoidentifythemostimportantopportunitiesisinplace,thetranslationalresearcheffortcanbeenhancedintwocomplementaryways.Thefirstisto
6 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Summary Vision
establishaproactive,highlyfacilitatedfundingprogramtoadvanceaselectnumberofthehighestpriorityopportunitiesthroughthedevelopmentprocessasefficientlyandeffectivelyaspossible.ThesecondistousetheidentifiedprioritiestoinformfundingdecisionsandthedevelopmentofnewinitiativeswithinthebroadertranslationalresearchportfolioacrosstheInstitute.
Forenhancedearlytranslationalresearchcoordinationandprioritizationtobeoptimallyeffective,fundingprogramsmustbestructuredtoadvanceprojectsdownadevelopmentalpathwayinafocused,milestone-driven,andgoal-orientedfashion.Suchprogramsmusthaveguidelines,incentives,andawardstructuresdesignedtofacilitatetimelydevelopmentalprogresstowardaspecificclinicalgoalratherthantoadvancescientificknowledgeoridentifynewresearchopportunities.Theselattergoalsarecentraltodiscoveryresearch,andremainimportantancillarygoalsfortranslationalresearch,buttheprimarypurposeoftranslationalprogressispatientandpublichealthbenefit.Moreover,becauseoftheircomplex,multidisciplinarynature,earlytranslationalresearchprojectsneedmoreactivemanagementtoensurethatneededresourcesareavailableandthatdiverseparticipantsandactivitiesarecoordinatedacrossthevariousstagesofdevelopment.Efficienttranslationalprogresswillalsorequireintegrationbetweenawardprogramsthatfunddifferentportionsofthedevelopmentalpathwaysandtimelyhandofftolate-stageclinicaltrials.
Enhancingearlytranslationalresearchproductivitywillalsorequireimprovementsinseveralaspectsofoperatingefficiency.High-quality,cost-effectivecoreservices,frommolecularanalysistomanufacturing,mustbereadilyaccessibletoallprojectsandinvestigators.Thisisespeciallytrueforstandardized,annotatedbiospecimens,whichareanessentialfoundationforkeyelementsoftranslationalprogress.Improvedtrainingandcareerincentiveswillbeessentialtoensureaworkforcecommittedtoearlytranslationalresearchthatiscontinuallyrefreshedbynewgenerationsofclinicalandlaboratoryresearchers.Collaboration,notonlyamongNCI-fundedresearchersbutwithotherkeyplayerssuchasindustry,researchfoundations,healthcarepractitionersandotherhealthcareprofessionals,patients,andpatientadvocates,iscentraltothesuccessoftheearlytranslationalresearchendeavor,particularlyinthetransitiontolater-stagedevelopment.Successfulcollaborationamongallpartieswilldependonenhancedcommunicationandoutreach,broadparticipationinNCImanagementandprioritizationprocesses,morejointfundingopportunities,andstreamlinedprocessesforestablishingrelationships.
Toachievetheseobjectives,theTranslationalResearchWorkingGroup(TRWG)oftheNationalCancerAdvisoryBoard(NCAB)hasdevelopedadetailedblueprintfor“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”TheTRWGstrategyistobuildonthestrengthsofexistingearlytranslationalresearchendeavorsbyenhancingcoordination,prioritization,andoperationaleffectivenesswhiletailoringfundingprogramstofacilitatetranslationalprogress.Thestrategyrecognizesthekeyroleofcancercentersinprovidingastabletranslationalresearchinfrastructure,thestrongearlytranslationalresearchconductedthroughtheSpecializedCenters(P50)andvariouscooperativeagreementandcontract-basedprograms,andthemanyexcellentearlytranslationalresearchprojectssupportedthroughinvestigator-initiatedProgramProject(P01),R01,andZ01awards.TheproposedTRWGinitiativespreserveandstrengtheneachoftheseexistingcomponentswhilecreatingneworganizationalstructuresandprocessesthatwillenablethemtoworktogetherinamoreintegratedandcooperativeway.TheproposedinitiativesarealsointendedtocomplementandextendtheworkoftheClinicalTrialsWorkingGroup,whichfocuseditsinitiativesontheclinicaltrialsenterprise,especiallylate-stagetrials,andtheenablinginformaticsinfrastructureandapplicationscurrentlybeingdevelopedbytheNCICenterforBioinformaticsaspartofthecancerBiomedicalInformaticsGrid(caBIG™).
ExtramuralinvestigatorsandNCIstafffromthroughouttheInstitutewillbeaskedtocollaborateinensuringthattheNCIearlytranslationalresearchportfolioisappropriatelybalancedacrossdiseasesites,affectedpopulations,anddevelopmentalpathwaystoclinicalgoalswithappropriateattentiontoprojectstargetedatrarecancersandminority/underservedpopulations.Theywillalsobeaskedtoparticipateinidentifyingespeciallypromisingearlytranslationalresearchopportunitiesandtoincorporateidentifiedprioritiesintotheirresearchprograms.Milestone-based,goal-orientedprogresswillbecomethestandardforrewardingearlytranslationalresearch,andinvestigatorswillbeexpectedtocollaborateopenly,sharingresources,handingoffprojectstonewteamsofexpertsasdevelopmentwarrants,andmakingteamscienceareality.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 7
Report of the NCAB Translational Research Working Group—Summary Vision
Implementingthesechangeswillrequireastrong,committedeffortbyallstakeholdersaswellasamodest,focusedfinancialinvestment.Butthisinvestmentofbothtimeandmoneyiswelljustifiedtoensurethatthemuchlargerongoingnationalinvestmentinearlytranslationalresearchachievesthegoalofmovingimportantdiscoveriesmoreeffectivelytowardsuccessfulhumantesting.Byembracingtheseinitiatives,NCIandthecancerearlytranslationalresearchcommunitywillenhancetheNation’seffectivenessandcompetitivenessinmeetingtheneedsandopportunitiesofcancerresearchasitevolvesintoaglobalpriority.Perhapsmoreimportantly,theNCI’scommitmenttotheseinitiativeswillalsodemonstrateastrongdedicationtoharnessingtheadvancesincancerbiologyachievedthroughthelast40yearsofresearchprogressforpatientandpublicbenefit.
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 9
Report of the NCAB Translational Research Working Group—Introduction
Introduction
InJune2005,theTranslationalResearchWorkingGroup(TRWG)wasestablishedundertheauspicesoftheNationalCancerAdvisoryBoard(NCAB)toadvisetheNationalCancerInstitute(NCI)onthefuturecourseofthiskeycomponentofNCI’sresearchportfolio.ThechargetotheTRWGwastoevaluatethecurrentstatusofNCI’sinvestmentintranslationalresearch,envisionitsfuture,anddeveloprecommendationsandimplementationplanstorealizethatvision.Thiseffortfollowed—andwasintendedtocomplementandextend—theworkoftheClinicalTrialsWorkingGroup,whichhadjustcompletedasimilarprocessrelatedtoclinicaltrials.TheTRWGisabroadlyconstitutedpanelofacademictranslationalresearchers,representativesfromindustryandfoundations,patientadvocates,andNCIstaff.ThemembershipoftheTRWGisprovidedatthefrontofthisreport.
Inordertofullyunderstandthecontextforitscharge,theTRWGbeganitsworkwithadetailedreviewof11prioranalysesandrecommendationsforimprovingtranslationalresearch.ThisincludedthePresident’sCancerPanel2004-2005AnnualReport;theNCAB1994CancerataCrossroadsReport;theNCABP30/P50AdHocWorkingGroupReport;theNCABClinicalTrialsWorkingGroupReport;severalNCIProgressReviewReports;theNIHRoadmapforMedicalResearch;andtheFoodandDrugAdministrationCriticalPathInitiativeReport(seeAppendixAforcitations).TheTRWGalsoreviewedseveralpublishedarticlesonthepromiseandchallengesoftranslationalresearch.
Tofurtherguideandinformitsdeliberations,theTRWGdevelopedanoperationaldefinitionoftranslationalresearchandselectedthe“earlytranslationalresearch”portionofthePresident’sCancerPanelTranslationalContinuumasthefocusforitsdeliberations(seeAppendixB).Basedonthedefinitionofearlytranslationalresearchasextendingfromacredentialeddiscoveryinthelab,clinic,orpopulationtothepointofearlyhumantesting,theTRWGdraftedsixdevelopmentalpathwaystoclinicalgoals:biospecimen-basedriskassessmentdevices,image-basedriskassessmentagents/techniques,agents,immuneresponsemodifiers,interventivedevices,andlifestylealterations(seeAppendixC).Byclearlydefiningthestepsinvolvedinearlytranslationalresearchanddistinguishingitfromdiscoveryresearch,thesepathwaysservedasavaluabletoolforunderstandingbarriersandchallengesinthecurrentsystemandforidentifyingareasinneedofimprovement.
TounderstandthenatureandscopeofNCI’scurrenttranslationalresearchactivity,theTRWGcommissionedacomprehensiveanalysisoftheFY04awardportfolio,includinginvestigator-initiated,solicited,andinfrastructureawards(seeAppendixD).ThisportfolioanalysisrevealedthattranslationalresearchawardsarecurrentlydistributedovermostDivisions,Centers,andOfficesandfundedbyarangeofprograms.However,theanalysisalsorevealedthatawardsarenotcurrentlycategorizedinamannerthatprovidesanaccurateassessmentoftranslationalcontent.TheTRWGalsocommissionedananalysisof20NCI-supportedtranslationalresearchsuccessestodeterminewhethertherewerecommonelementsorthemesthatcontributedtothosesuccesses(seeAppendixE).Theseanalysesdemonstratedthatsuccessfultranslationoccursthroughadiverserangeoffundingprogramsandstakeholderinteractions.
TheTRWGconductedsevenface-to-facemeetingsfromDecember2005throughJanuary2007.Toaccomplishitswork,theTRWGorganizeditselfintosubcommitteesresponsiblefordifferentaspectsoftranslationalresearch.Duringtheplenarymeetings,eachsubcommitteereportedontheprogressofitsworkandsolicitedcommentsfromtheTRWGasawhole.Betweenplenarymeetings,thesubcommitteesconductedasubstantialnumberofconferencecallsamongthemselvesandwithnon-TRWGexpertstodevelopandrefinetheirproposals.Furthermore,duringthisprocess,theexternalcommunityprovidedsubstantive,real-timeinputintothedevelopmentoftheTRWGrecommendationsthroughtwoimportantvenues—Internet-basedpublicforumsandinvitedRoundtableMeetings.
DuringthefirstInternetforum,conductedDecember2005throughJanuary2006,1theTRWGsoughtpublicinputonvarioustranslationalresearchissuesincludingbarriers,incentives,prioritization,funding,systemorganization,facilities/technologies,andmanpower/training.AttheinitialRoundtableMeeting,heldinFebruary2006,theTRWGsolicitedinputfromabroadarrayofcancercommunitystakeholdersonissuesintranslationalresearchandrecommendationsfor
1 MeetingdatesarelistedinAppendixF.
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Report of the NCAB Translational Research Working Group—Introduction
improvementfromthreedifferentperspectives:a)theTRWGpathwaystoclinicalgoals;b)populationsserved;andc)cross-cuttingthemessuchasfunding,organization,coordination,facilities/technologies,workforce/training,andindustryinteractions.AnIndustry/Society/FoundationRoundtable,heldinApril2006,providedanopportunityfortheTRWGtogatherinputfrompharmaceutical,biotechnology,anddevicecompaniesaswellascancersocietiesandfoundations.ThediscussionsatthisRoundtablefocusedonissuesofresources,collaboration,andmanagementintranslationalresearchaswellastheutilityoftheTRWGpathwaysastoolsfordevelopingandguidingresearchplans.DuringthesecondInternetforuminOctober2006,theTRWGrequestedpubliccommentonthedraftinitiativesandimplementationconcepts.DuringthefinalRoundtableMeeting,alsoheldinOctober2006,theTRWGrequestedcommentsanddiscussionconcerningthedraftinitiativesandtheirassociatedimplementationconcepts,againfromtheperspectiveofthedifferentTRWGdevelopmentalpathwaysandpopulationsserved.
InadditiontotheInternetforumsandRoundtableMeetings,theTRWGalsoreceivedvaluableinputfromtheAmericanAssociationforCancerResearch,theAmericanSocietyofClinicalOncologyTranslationalResearchTaskForce,theOncologyNursingSociety,theCancerBiologyTrainingConsortium,theUKMedicalResearchCouncil,theNationalInstituteofNeurologicalDiseasesandStroke,andtheDirectorsoftheSpecializedProgramsinResearchExcellence,theEarlyDetectionResearchNetwork,andthecancercenters.
Initsdeliberations,theTRWGreachedconsensusthroughfoursequentialstages.Thefirststagewastodefinethefollowinglistofcurrentchallengestothesuccessofearlytranslationalresearch:
1. Insufficientcoordinationandintegrationresultsinafragmentedtranslationalresearcheffortthatrisksduplicationandmaymissimportantopportunities.
2. AbsenceofclearlydesignatedfundingandadequateincentivesforresearchersthreatenstheperceivedimportanceoftranslationalresearchwithintheNCIenterprise.
3. Absenceofastructured,consistentreviewandprioritizationprocesstailoredtothecharacteristicsandgoalsoftranslationalresearchmakesitdifficulttodirectresourcestocriticalneedsandopportunities.
4. Themultidisciplinarynatureoftranslationalresearchandtheneedtointegratesequentialstepsincomplexdevelopmentalpathwayswarrantdedicatedprojectmanagementresources.
5. Translationalresearchcoreservicescanbeduplicativeandinconsistentlystandardized,withcapacitypoorlymatchedtoneed.
6. Inadequatecollaborationwithindustrydelaysappropriatedevelopmentalhandoffs.
7. Extendednegotiationonintellectualpropertyissuesdelaysorpreventspotentiallyproductivecollaborations.
8. Inadequatecollaborationwithfoundations/advocacygroupsrisksmissingimportantopportunitiesforpatientoutreachandintegrationoftranslationalresearchefforts.
9. Insufficientcollaborationandcommunicationbetweenbasicandclinicalscientistsandthepaucityofeffectivetrainingopportunitieslimitsthesupplyofexperiencedtranslationalresearchers.
TheTRWGthendefinedspecificimprovementsinthecurrentNCI-supportedearlytranslationalresearchenterprisetoaddresstheseobstacles.
Thesecondstagewastodeveloprecommendationsaddressingthemostimportantimprovements.Aninitialgroupofrecommendationsconcerningorganizationandfunding,prioritization,coreservices,andprojectmanagementwerepresentedtotheNCABonJune14,2006.Duringthethirdstage,additionalrecommendationsweredeveloped,focusingonexternalintegrationandworkforce/training.Finally,duringthefourthstage,specificinitiativesandimplementation
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 11
Report of the NCAB Translational Research Working Group—Introduction
plansweredevelopedaddressingthevariousrecommendations.Thegoalwastodevelopproposedimplementationplansthatwouldbeinnovative,yetpractical,andwouldbuildonthebestofthecurrentNCIearlytranslationalresearchsystem.
Thisconsensus-buildingprocessresultedinthe15initiativesdetailedinthisreport,“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”TheseinitiativesarenotintendedtoaddressNCIeffortsinotherareasoftheTranslationalResearchContinuumasdefinedbythePresident’sCancerPanel,includingbasicsciencediscovery,latetranslation(PhaseIIItrials),dissemination,andadoption.
Theproposedinitiativesareorganizedintothreecategories:CoordinatedManagement,TailoredFundingPrograms,andOperationalEffectiveness.TheCoordinatedManagementInitiativesestablishanintegratedorganizationalapproachacrossNCItocoordinateandprioritizeearlytranslationalresearch,designateaspecificportionoftheNCIbudgetforearlytranslationalresearch,andimprovethecodingofearlytranslationalresearchawards.TheTailoredFundingProgramsInitiativesestablishnewfundingprogramstailoredtothedistinctivecharacteristicsofearlytranslationalresearchandmodifyexistingprogramstoenhancetranslationalproductivity.TheOperationalEffectivenessInitiativesimprovetheconductofearlytranslationalresearchbyestablishingaformalprojectmanagementsystem,coordinatingcoreservices,improvingbiospecimenresources,facilitatingindustryandfoundationcollaborations,andenhancingworkforcedevelopment.EachinitiativealsohasaproposedimplementationtimelineandbudgetpresentedinaconsolidatedTimelineandBudgetsection.
EachoftheinitiativespresentedinthisreportwascreatedtoaddressacriticalissuefortranslationalprogressandrepresentsanessentialgoalaboutwhichthereisstrongconsensusamongtheTRWGmembership.Foreachinitiative,theTRWGdevelopedarationalethatsupportsthegoaloftheinitiativeandservedasapremisefortheimplementationstrategy.TheTRWGthengavecarefulconsiderationtodevelopingconstructiveideasforimplementationstepsthatcouldmosteffectivelyachievethestatedgoals.Theseproposedimplementationplansattempttobalancetherequirementsoftheinitiativesagainsttherealitiesandconstraintsofcurrentstructural,functional,economic,andpoliticalenvironments.TheTRWGhopestheseideaswillbegivencarefulconsideration;theyarenotintendedtoconstrainNCI’soptionsforachievingthegoalsbut,rather,toenhanceitssuccessindoingso.
Nomajormodificationtoanongoingenterprise,suchasthatrecommendedbytheTRWG,shouldbeundertakenwithoutestablishingamechanismforevaluatingitssuccess.Accordingly,thisreportincludesasectiononEvaluationandOutcomesthatoutlinestheprocessrecommendedbytheTRWGforevaluatingtheimplementationandimpactoftheproposedinitiatives.
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 13
Report of the NCAB Translational Research Working Group—Coordinated Management
Coordinated Management
Introduction
TheTRWGportfolioanalysisrevealedthatearlytranslationalresearchissupportedbyawidevarietyofprogramsmanagedthroughvirtuallyallNCIDivisions,Centers,andOffices.Coordinationoftranslationalresearchactivitiesacrosstheseprogramsandorganizationalstructuresiscurrentlyinformalandprojectorissuespecific,whichcanresultinduplication,missedopportunities,andlackofsynergy.Amoreintegratedmanagementapproachhasthepotentialtodevelopasharedvisionforthegoalsoftheoverallenterpriseandincreasetheefficiency,productivity,andtransparencyofNCI-supportedearlytranslationalresearch.
AmorecoordinatedNCIorganizationalstructureforearlytranslationalresearchwilltakebetteradvantageoftherespectivescientificandmanagerialstrengthsoftheexistingDivisions,Centers,andOfficesandfacilitatecomprehensiveextramuraladviceandoversight.Akeymanagementtoolwillbeasharedunderstandingofthenatureandscopeoftheearlytranslationalresearchportfolioatboththeprogramandawardlevel.Suchanunderstandingisessentialtoidentifypotentialgaps,redundancies,andsynergiesacrossprojectsandprograms.Coupledwithabudgettargetforearlytranslationalresearch,italsowillfacilitatelong-termplanningandthebalancingofinvestmentsacrossdiseasesites,populations,andthesixTRWGdevelopmentalpathways.
AnotherkeymanagementtoolwillbeasystematicprioritizationprocessdrawingoninputfromallNCIDivisions,Centers,andOfficesandthebroadextramuralcommunity,includingawiderangeofhealthcareprofessionals,patientadvocates,andtheothergovernmentagenciesandfoundationsactiveincancerresearch.Theprocesswillbedesignedtoidentifytranslationalopportunitiesmostpromisingfordevelopmentbaseduponscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimportance,includingtheneedsofthosewithrarecancersandmedicallyunderservedpopulations.
Tobuildacoordinatedmanagementapproachthatincorporatestheseelements,theTRWGproposesfourinitiatives.
A1. Establish a flexible, integrated organizational approach that coordinates early translational research across the National Cancer Institute.
A2. Designate a specific portion of the National Cancer Institute budget for early translational research.
A3. Develop a set of award codes that accurately capture the nature and scope of the early translational research portfolio.
A4. Establish a distinctive prioritization process for early translational research.
14 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Coordinated Management
Initiative A1: Establish a flexible, integrated organizational approach that coordinates early translational research across the National Cancer Institute.
Rationale
Translationalresearchisintendedtomoveadiscoveryorsetofdiscoveriesthroughafocuseddevelopmentprocesstothepointofearlyhumantesting(seethesixTRWGdevelopmentalpathwaysinAppendixC).Becauseofthecomplex,multidisciplinary,goal-oriented,fast-paced,andtime-sensitivenatureofthisdevelopmentprocess,translationalresearchrequiresamoreintegratedandcoordinatedmanagementapproachthanwouldbeappropriatefordiscoveryresearch.
Currently,NCI-fundedtranslationalresearchprojectsaremanagedbyindividualprogramsdistributedacrossvirtuallyallDivisions,Centers,andOffices.Coordinationacrossprogramsandorganizationalstructuresisgenerallyinformalandsituational,whichresultsinthepotentialforoverlap,duplication,missedopportunities,andotherinefficiencies.Thisdistributedapproachcanmakeitchallengingtoidentifypotentialsynergiesandtoredirectenergiesandresourcestoemergingopportunitiesinatimelymanner,andcanleadtoalackoffocusintranslationalresearchgoalsandprograms.Whilethescientificqualityoftheindividualresearchprojectsandprogramsisveryhigh,integratingtheprogramsmoreformallyandsubstantivelywouldenhancetheefficiencyandproductivityoftheenterpriseasawhole.
ManyoftheTRWGinitiativesaredesignedtoimprovecoordinationandintegrationoftranslationalresearchacrossprojectsandprograms,bothamonginvestigators,institutions,andNCI,andwithexternalstakeholderssuchasindustry,foundations,andadvocacygroups.However,tofullyrealizetheirpotential,theseinitiativesmustbeguidedbyacohesiveandcoordinatedNCIorganizationalstructurethatisfocusedspecificallyontheneedsoftranslationalresearchanddedicatedtoitsvitality.Suchacoordinatedstructureisnecessarytoeffectivelymanagetheoveralltranslationalresearchportfolio;reducefragmentationandredundancy;ensurethatrarecancers,medicallyunderservedpopulations,andhistoricallylower-resourcedpathwaystoclinicalgoalsareappropriatelyaddressed;andallocateresourcesacrosstheenterpriseformaximumoverallbenefit.Thiscomprehensivecoordinationisespeciallyimportanttodaygiventheanticipatedrapidpaceofcancerdiscoveriesandtheresultingneedforadaptivestructuresandfunctionstomanageandguidetheoverallenterprise.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
InordertoestablishamoreintegratedandcoordinatedmanagementapproachfortranslationalresearchacrossNCI,threecriticalorganizationalelementswillbeestablished.Thefirstisformalextramuraladviceandoversightspecificallyfortranslationalresearch,whichtheTRWGrecommendsbevestedinthenewClinicalTrialsAdvisoryCommitteeestablishedasaresultoftheClinicalTrialsWorkingGroupReport.ThesecondelementisaTranslationalResearchOperationsCommitteeinvolvingtheDirectors(ordesignees)ofallNCIDivisions,Centers,andOfficeswithresponsibilityfortranslationalresearchprogramsinamatrixmanagementstructureresponsibleforcoordinatingandintegratingtranslationalresearchactivitiesacrosstheInstitute.ThethirdelementisaTranslationalResearchSupportOfficewithinthenewCoordinatingCenterforClinicalTrialsestablishedasaresultoftheClinicalTrialsWorkingGroupReport.ThisSupportOfficewillberesponsibleforsupportingtheTranslationalResearchOperationsCommitteeandfacilitatingandcoordinatingimplementationofalloftheTRWGinitiatives.ThiscoordinatedmanagementstructureisdepictedinFigure2,page15.
Leadership Focus
AstrongfocusfortranslationalresearchwithintheOfficeoftheDirectorisessentialtoprovidecleardirectionforthefutureofNCI-fundedtranslationalresearchandensurethatissuesrelatedtotranslationalresearchhaveadedicated,coordinatedvoicewithintheNCIseniorleadershipteam.Thisleadershiprolefortranslationalresearchwillbeeither
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assumedbytheNCIDirectorordelegatedbytheDirectortoaseniortranslationalresearcherwhoisatthelevelofaDivisionDirectorandservesontheExecutiveCommittee.ToensurecommitmenttothebroadtranslationalmissionoftheInstituteratherthananysinglecomponent,thisindividualideallywouldnotbeastandingDirectorofaDivision,Center,orOffice.IftheNCIDirectorelectstodelegatethisresponsibility,thedesigneeshouldhaveanationallyrecognizedscientificreputationintranslationalresearchandexperiencemanagingorganizationscarryingouttranslationalresearch.TheindividualshouldalsohaveexperiencewithNCIoperations,possiblythroughservingonNCIadvisorycommittees(e.g.,NationalCancerAdvisoryBoard(NCAB),AdvisoryCommitteeoftheDirector(ACD),BoardofScientificAdvisors(BSA),BoardofScientificCounselorsforBasicSciences,BoardofScientificCounselorsforClinicalSciencesandEpidemiology).
TheNCIDirectorordesigneewillserveasChairoftheTranslationalResearchOperationsCommittee(discussedbelow).TheChairwillberesponsibleforensuringthattheCommitteefunctionsasacohesiveteamtoadvancetranslationalresearchinacoordinatedandbalancedmanneracrossNCI.AparticularlyimportantresponsibilitywillbetoguidetheCommitteethroughanannualreviewoftheNCItranslationalresearchportfolioinordertoachieveaconsensusrecommendationonanintegratedprogramandbudgetacrossallDivisions,Centers,andOffices.
Translational Research External Advisory Oversight
AsaresultoftheinitiativesrecommendedbytheClinicalTrialsWorkingGroup,anewexternaladvisorycommittee,theClinicalTrialsAdvisoryCommittee,hasrecentlybeenestablishedtoadvisetheNCIDirectorontheconductofclinicalresearchacrosstheInstitute.TheTRWGiskeenlyawarethatthebenefitsofasimilarlyfocusedandinformedoversightgroupfortranslationalresearchmustbebalancedagainstthepotentialcostsandcomplexitiesofsuchanundertaking.Therefore,theTRWGrecommendsthattheresponsibilitiesofthenewClinicalTrialsAdvisoryCommitteebeextendedtoincludeoversightoftranslationalresearchandthatNCIconsiderchangingthenameofthiscommitteetotheClinicalandTranslationalAdvisoryCommittee.(Hereafterinthisreport,theCommitteewillbereferredtosimplyasthe“AdvisoryCommittee”whendiscussingitstranslationalresearchresponsibilities.)AlthoughseveralnewlyappointedmembersoftheAdvisoryCommitteeareexperiencedtranslationalresearchers,theTRWGrecommendsthatthemembershipbereviewedandexpandedasnecessarytoensurethatatleast50%ofthemembershavetranslationalresearchexpertise.
Therationaleforthisapproachisfourfold.First,thenewAdvisoryCommitteealreadyhasoversightresponsibilitynotonlyforlate-stageclinicaltrials,butalsoforearly-stagetrials,whichareanintegralpartofearlytranslationalresearch.Second,theAdvisoryCommitteehasresponsibilityforcertaincorrelativesciencestudies,whichmayinformnonclinicaldiscoveryandtranslationalresearchactivities.Third,integratedoversightwillfacilitatecoordinationoftheprioritizationprocessesforearlytranslationalresearchandlater-stageclinicaltrials.
Thefourth,andmostimportant,rationaleisthatrapidadvancesincancerbiology,whichenhanceourunderstandingofthegeneticandcellularmechanismsunderlyingspecificcancers,aremakingpossiblethescientificallydrivendevelopmentandclinicaltestingofnovelinterventionstargetedatthespecificcharacteristicsofapatient’stumororunderlyinggeneticprofile.Capitalizingontheseadvanceswillrequireclosecollaborationamongtranslationalscientistsandtheclinicalresearchersresponsibleforbothearly-andlate-stagetrials.Thededicatedhigh-levelattentionprovidedbyacoordinated
Figure 2. Coordinated NCI Organizational Structure
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extramuraloversightbodyisneededtoensurethattheseadvancesinmolecularmedicinemoveforwardthroughdevelopmentandclinicaltrialsinacoordinatedandefficientfashion.
InvestingoversightresponsibilityfortranslationalresearchintheAdvisoryCommitteeratherthanNCI’sotheradvisorycommittees(e.g.,NCAB,ACD,BSA,theBoardsofScientificCounselors)isrecommendedbecausetheseothercommitteesarechargedwithadvisingtheDirectoronallaspectsofcancerresearch,ratherthanfocusingspecificallyonindividualcomponentsoftheenterprise.Incontrast,mergingoversightresponsibilityforearlytranslationalresearchwiththatforclinicaltrialswillprovideefficient,focusedoversightforbothcriticalcomponentsoftheoveralltranslationalresearchcontinuumacrossboththeintra-andextramuralcommunities.
TheAdvisoryCommitteewillhavethefollowingresponsibilitieswithregardtoearlytranslationalresearch:
1. AdvisetheDirectorontheeffectivenessofNCI’stranslationalresearchmanagementandadministrationacrossallDivisions/Centers/Officesinmeetingdemandsandopportunitiesacrossdiseasesites,patientpopulations,thesixTRWGdevelopmentalpathways,andtherangeofmolecularmechanismsresponsibleforcancerdevelopment,andmakerecommendationsforneededimprovementsandfuturedirections.
2. AdvisetheDirectorontheoperationsandactivitiesoftheTranslationalResearchOperationsCommittee(describedbelow).
3. AdvisetheDirectorandExecutiveCommitteeontheappropriatemagnitudeforthededicatedtranslationalresearchbudgettarget(seeCoordinatedManagementInitiativeA2)andrecommendallocationoftranslationalresearchfundingacrossorganizationalunits,programs,diseasesites,populations,developmentalpathways,andmolecularmechanisms.
4. Ensurethatappropriateemphasisisplacedonidentifyingresearchneedsandprioritiesforrarecancers,medicallyunderservedpopulations,andhistoricallylower-resourcedpathwaystoclinicalgoals(e.g.,immunotherapy,interventivedevices,lifestyleinterventions).
5. RecommendtotheDirectortranslationalresearchprioritiesbasedonthenew,system-widetranslationalresearchprioritizationprocess(seeCoordinatedManagementInitiativeA4).
Translational Research Operations Committee
Giventhenumber,breadth,andpaceofearlytranslationalresearchactivitiesunderwayacrossNCIDivisions,Centers,andOffices,itisessentialtocreateaninternalmanagementstructurethatcancoordinateandintegratetheseactivitiesandrespondtoemergingopportunities.Tothatend,aTranslationalResearchOperationsCommitteewillbeestablishedthatincludestheDirectors(ordesignees)ofallNCIDivisions,Centers,andOfficeswithresponsibilityforsubstantialearlytranslationalresearchprograms.TheCommitteewillbechairedbytheNCIDirectorortheindividualdesignatedbytheDirectortoleadtranslationalresearchacrossNCI(seeabove).
Aswiththeexternaladvisoryrole,theTRWGconsideredtheadvantagesanddisadvantagesoftaskinganexistingbody,suchastheExecutiveCommittee,withtheresponsibilitiesenvisionedforthisnewcommittee.Inthiscase,however,anew,dedicatedcommitteeseemedthemosteffectiveapproachgiventherequirementforactivemanagementandtheoperationalchallengestobeaddressed.SuchanewOperationsCommitteewillconstituteanefficientmanagementtoolandforumtoensurethattranslationalresearchissuesareaddressedwithadedicatedtimeandagendathatcannotbedivertedtootherpressingmatters.
Membership. GivenNCI’scurrenttranslationalresearchportfolio,initialmembershipoftheTranslationalResearchOperationsCommitteewillbetheDirectors(ordesignees)fromthefollowingNCIorganizationalunits:
• DivisionofCancerPrevention
• DivisionofCancerTreatmentandDiagnosis
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• DivisionofCancerBiology
• DivisionofCancerControlandPopulationSciences
• DivisionofCancerEpidemiologyandGenetics
• OfficeofCenters,Training,andResources
• CenterforCancerResearch
• OfficeofTechnologyandIndustrialRelations
• CenterforBioinformatics
• DivisionofExtramuralActivities.
OtherNCIentities—suchastheOfficeofSciencePlanningandAssessment,theOfficeofLegislativeAffairs,andtheTechnologyTransferBranch—willberepresentedontheOperationsCommitteeonanadhoc,nonvotingbasis.
Coordination of Translational Research Portfolio. TheTranslationalResearchOperationsCommitteewill,onanannualbasis,reviewandprioritizethetranslationalresearchportfolioproposedbyeachDivision,Center,andOfficewiththegoalofbalancing,coordinating,andintegratingtranslationalresearchacrossNCI.PrioritizationofnewinitiativesandguidancetoprogramstaffconcerningR01andP01prioritieswillbebasedontheprioritiesresultingfromthenewprioritizationprocess(seeCoordinatedManagementInitiativeA4),aswellasequitablebalanceacrossdiseasesites,populations,andtheTRWGdevelopmentalpathways,alongwithspecialattentiontotheneedsofrarecancersandminorityorunderservedpopulations.TheCommitteewillreviewandapprovealltranslationalresearchProgramAnnouncements(PAs)andRequestsforApplications(RFAs)priortosubmissiontotheExecutiveCommittee.
Development of an Integrated Translational Research Program Budget. TheOperationsCommitteewilldevelopanintegratedtranslationalresearchprogrambudgetthatwillberecommendedtotheExecutiveCommitteeandtheNCIDirectorforuseinNCI-widebudgetdeliberations.This“translationalresearchbudget”willrepresentamatrixoftheportionofeachDivision,Center,andOfficebudgetdevotedtotranslationalresearch.
ThematrixtranslationalresearchbudgetwillinitiallyinvolveallRFA-andPA-directedprogramsidentifiedbytheOperationsCommitteeasfocusedonearlytranslationalresearch.ThesewilllikelyincludetheSpecializedProgramsofResearchExcellence(SPORE),EarlyDetectionResearchNetwork(EDRN),In VivoCancerMolecularImagingCenters(ICMIC),NationalCooperativeDrugDiscoveryGroups(NCDDGs),RapidAccesstoInterventionDevelopment(RAID)/RapidAccesstoPreventiveInterventionDevelopment(RAPID)/DevelopmentofClinicalImagingDrugsandEnhancers(DCIDE)programs,andprojectsfundedthroughPAsandRFAsidentifiedas“translational.”ThePhaseIandPhaseIIclinicaltrialcontractswilleitherbeincludedinthisbudgetoraspartoftheclinicaltrialsbudgetmanagedbytheClinicalTrialsOperationsCommitteeformedinresponsetotheClinicalTrialsWorkingGroupReport.
Whilethisinitialgroupofprojectswillnotdefinethecompletetranslationalresearchbudget,itwillrepresentacoresetoftranslationalresearchactivities.ThiswillallowtheOperationsCommitteetomakeaninitialevaluationofthetranslationalresearchbudgetwithregardtothefollowing:
• OverallsizerelativetothetotalNCIresearchbudget
• AllocationacrossDivisions,Centers,andOffices
• PercentageoffundingfromeachDivision,Center,andOfficedesignatedfortranslationalresearch
• Allocationacrossfundingprograms
• Allocationacrossdiseasesites
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• Allocationacrosspopulations
• Allocationacrossprevention,therapy,riskassessment,etc.
• AllocationacrossthesixTRWGdevelopmentalpathways
• Allocationacrosstopicsofinterest(e.g.,explorationofspecificmechanismsofcancerdevelopment,specifictechnologies,corefacilities).
Asthecodingsystemandportfolioanalysistechniquesimprove(seeCoordinatedManagementInitiativeA3),theintegratedbudgetwillbeexpandedtoincludeR01andP01andZ01awardsthatarecodedastranslational,trainingawardsfromprogramsidentifiedasapplicabletotranslationalresearchers(e.g.,K12,K23,K24),andawardsfromothermechanismsidentifiedbytheTRWGportfolioanalysisasbeingmorethan50%translational(e.g.,SmallBusinessInnovationResearchProgram[SBIR]/SmallBusinessTechnologyTransferProgram[STTR]).ThiswillallowtheOperationsCommitteetofurtherrefineitsmanagementoftranslationalresearchfundingacrossNCI.
Oncetheintegratedtranslationalbudgetanditsassociatedportfolioanalysisareavailableinacomprehensivefashion,theOperationsCommitteewillbeabletoidentifygaps,overlaps,andopportunities.Thesecanthenbeusedasthebasisfordevelopingandsustaininga5-yearrollingplanandbudgettoguidethefutureoftranslationalresearch.SuchaplanwillallowNCItochartfutureobligationsassociatedwithalready-fundedtranslationalresearchawardsaswellasanalyzetradeoffsthatmayberequiredamongfundingexistingprograms,fundingnewTRWG-recommendedprograms(seeTailoredFundingProgramsInitiativesB3andB4),andfundingothernewprograms.
Additional Responsibilities. Inadditiontothemajorresponsibilitiesdescribedabove,theTranslationalResearchOperationsCommitteewillberesponsibleforthefollowingtasksinconsultationwiththeAdvisoryCommittee:
1. EvaluateorganizationalinfrastructuresandoperatingbudgetsfortranslationalresearchprogramsupportacrossallDivisions,Centers,andOffices,andmakerecommendationsasnecessarytoimprovecost-effectivenessandreduceduplicationandoverlap.
2. RefinetheTRWGoperationaldefinitionof“translationalresearch,”asdistinguishedfromdiscoveryorclinicalresearch,andapproveanewcodingsystemthatwillallowtheNCItranslationalresearchportfoliotobeidentifiedandtrackedaccurately.
3. Identifyfutureopportunitiesforprogrammaticimprovement,whetherthroughnewpartnerships(industry,foundations,trans-NIH),newcollaborationsacrossNCIgrantees,newintramural-extramuralpartnershipsandcollaborativeactivities,oridentificationofemergingbarriers/roadblockstotranslationalsuccess.
4. OverseeandcoordinateimplementationoftheTRWGinitiatives.
Translational Research Support Office
TomanageimplementationoftheTRWGinitiativesandsupporttheTranslationalResearchOperationsCommitteeandtheAdvisoryCommittee,aTranslationalResearchSupportOffice(TRSO)willbecreatedwithintheCoordinatingCenterforClinicalTrials(CCCT)recentlyestablishedintheOfficeoftheDirectorasaresultoftheClinicalTrialsWorkingGroupprocess.SuchanexpansionoftheCCCT’sresponsibilitieswillrequirecreatingtwodistinctbutintegratedofficesundermanagementofacenterdirector.Oneofficewillhaveprimaryresponsibilityforclinicaltrialsissuesandtheotherwillhaveprimaryresponsibilityfortranslationalresearchissues.
Thisorganizationalstructurewillhaveseveralbenefits.First,itwillensurethatactivitiesattheintersectionoftranslationalandclinicalresearch(e.g.,early-stagetrials)arewellintegrated.Second,itwillfacilitatecreationofacadreofprofessionalswhoarecross-trainedandabletocontributebothoperationallyandstrategicallytoactivitiesthatimpact
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eithertranslationalorclinicalresearch,regardlessoftheirprimaryfocusofresponsibility.Finally,itwillallowmoreefficientuseofadministrativesupportandorganizationalservices.
Staffing. TheSupportOfficestaff,whichwillbephased-inovertimetosupportimplementationoftheTRWGinitiatives,willbeprimarilyprofessionalstaff.TheheadoftheOfficewillbeatranslationalresearcherandmanager,preferablywithexperienceinboththeextramuralcommunityandatNCI.HeorshewillberesponsibleformanagementoftheOfficeanditsintegrationwithoverallactivitiesoftheexpandedCoordinatingCenter.TheprofessionalstaffwillhavetranslationalresearchexperienceineitheracademiaorindustryaswellasexperienceinNCIextramuralprogrammanagementorreview.TheSupportOfficewillalsoincludeindividualswithtranslationalresearchprojectmanagementexperienceineitherindustryoracademia(seeOperationalEffectivenessInitiativeC1).ManySupportOfficeresponsibilitieswillbeimplementedwiththeassistanceofcontractorsandotherNCIstaff;however,thoseactivitieswillbedirectedandcoordinatedbySupportOfficestaff.
Responsibilities. TheTRSOwillhavethefollowingresponsibilities:
1. Manageoperationofthenewtranslationalresearchprioritizationsystem(seeCoordinatedManagementInitiativeA4),includinggatheringandanalyzinginputfromthebroadcancerresearchcommunityandoverseeingtheportfolioanalysisofongoingNCI-fundedactivities.
2. ProvidesupportfortheTranslationalResearchOperationsCommittee,especiallyinoverseeingportfolioanalysesanddevelopingtheintegratedtranslationalresearchbudget.
3. ServeasprogramofficersandprojectmanagersfortheSpecialTranslationalResearchAccelerationProject(STRAP)programandtheacademic/industrycollaborationprogram(seeTailoredFundingProgramsInitiativesB3andB4).2
4. ProvideprojectmanagementsupportandcoordinationtoprojectmanagersandprogramofficersintheDivisions/Centers/Officesinexecutingtheirprojectmanagementresponsibilitiesformultiprojectcollaborativeawards,includingP50andU-seriesawards.
5. ManageimplementationoftheremainingTRWGinitiativesinconsultationwithNCIleadershipandprogramstaff:
Newcodingsystemfortranslationalresearchawards
Modificationsofguidelinesformultiprojectcollaborativetranslationalresearchawards
CollaborationacrossNIHtocreatenewR-seriesandP-seriesmechanismstailoredtotranslationalresearch
Integrationoffundingprogramsforpharmacology,toxicology,andmanufacturingserviceswithfundingprogramsforotherstepsintranslationalresearch
Coreservicescoordinationandcreationofregionalcentersofexcellence
CollaborationwiththeOfficeofBiorepositoriesandBiospecimenResearchonenhancedqualityandaccessibilityofbiospecimenrepositories
Improvedpracticesfornegotiationofintellectualpropertymattersintranslationalresearch
Enhancedintegrationandcollaborationwithfoundationsandadvocacygroups
Improvedtrainingandcareerincentivesforthetranslationalresearchworkforce.
2 Foreachaward,TRSOstaffwillworkcloselywithadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperience.Astheprogramsexpand,programofficer/projectmanagerresponsibilitiesmaybeshiftedtotherelevantDivisionalstaffattimeofaward.
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Minority and Underserved Populations Working Group
Tofacilitatethefocusingoftranslationalresearchresourcesonunmetcancerresearchneedsassociatedwithminorityandunderservedpopulations,theTRWGrecommendsthattheAdvisoryCommitteeestablishaTranslationalResearchMinorityandUnderservedPopulationsWorkingGroupchargedwithmakingrecommendationswithregardtothefollowingareas:
1. Identifyinitialtargetsoftranslationalresearchneedandopportunitywithregardtothesespecialpopulations,usingprioritizationapproachessimilartothosedescribedinCoordinatedManagementInitiativeA4.
2. Developaprogrammaticstrategyforaddressingtheidentifiedtargets,includingtheappropriatemixofintramuralandextramuralactivities,thefundingvehiclesbestsuitedtofacilitatingtheextramuralcomponent,andapproachesforobtainingnewfundsorreprogrammingexistingfundsovertimetosupportthiseffort.
3. Designresearch-linkedtrainingopportunitiesthatwillengageyoungresearchersfromunderrepresentedpopulationsaswellasresearchersinterestedinaddressingtheunmetneedsofminorityandunderservedpopulations.
4. Developastrategyfornetworkingandcollaborationwithindustry,foundations,advocacygroups,communityorganizations,etc.,insupportoftheobjectivesofthiseffort,andfordisseminationofitspriorities,strategies,andresults.
TheTRWGrecommendsthattheWorkingGroupincludethefollowingmembers:
• AdvisoryCommitteememberswithtranslationalresearchexpertiserelevanttominorityandunderservedpopulations
• RepresentativesfromtheDirector’sConsumerLiaisonGroup
• Directors(ordesignees)ofallintramuralandextramuralDivisions,Centers,andOfficeswithprogramsrelevanttominorityandunderservedpopulations
• DirectoroftheNCICentertoReduceCancerHealthDisparities
• ChiefoftheComprehensiveMinorityBiomedicalBranchintheNCIOfficeofCenters,Training,andResources
• Cancerdisparitiesexperts
• Intramuraltranslationalresearchersfocusedontheneedsofminorityandunderservedpopulations
• Extramuraltranslationalresearchersfocusedontheneedsofminorityandunderservedpopulations
• Leadersofexistingcancerresearchinitiatives,networks,andconsortiaintheareasofminoritiesandunderservedpopulations
• Advocatesrepresentingpatientsfromminorityandunderservedpopulations
• Communityleadersrepresentingminorityandunderservedpopulations.
Rare and Pediatric Cancers Working Group
Tofacilitatethefocusingoftranslationalresearchresourcesonunmetneedsassociatedwithrarecancersandpediatriccancers,theTRWGrecommendsthattheAdvisoryCommitteeestablishaTranslationalResearchRareandPediatricCancersWorkingGroupchargedwithmakingrecommendationswithregardtothefollowingareas:
1. Identifyinitialtargetsoftranslationalresearchneedandopportunitywithregardtothesecancers,usingprioritizationapproachessimilartothosedescribedinCoordinatedManagementInitiativeA4.
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2. Developaprogrammaticstrategyforaddressingtheidentifiedtargets,includingtheappropriatemixofintramuralandextramuralactivities,thefundingvehiclesbestsuitedtofacilitatingtheextramuralcomponent,andapproachesforobtainingnewfundsorreprogrammingexistingfundsovertimetosupportthiseffort.
3. Designresearch-linkedtrainingopportunitiesthatwillengageyoungresearchersinterestedinaddressingtheunmetneedsofrareandpediatriccancers.
4. Developastrategyfornetworkingandcollaborationwithindustry,foundations,advocacygroups,etc.,insupportoftheobjectivesofthiseffort,andfordisseminationofitspriorities,strategies,andresults.
TheTRWGrecommendsthattheWorkingGroupincludethefollowingmembers:
• AdvisoryCommitteememberswithtranslationalresearchexpertiserelevanttorarecancersandpediatriccancers
• RepresentativesfromtheDirector’sConsumerLiaisonGroup
• Directors(ordesignees)ofallintramuralandextramuralDivisions,Centers,andOfficeswithprogramsrelevanttorarecancersandpediatriccancers
• Intramuraltranslationalresearchersfocusedontheneedsofpatientswithrarecancersandpediatriccancers
• Extramuraltranslationalresearchersfocusedontheneedsofpatientswithrarecancersandpediatriccancers
• Leadersofexistingcancerresearchinitiatives,networks,andconsortiaintheareasofrarecancersandpediatriccancers
• Advocatesrepresentingpediatriccancerpatientsandpatientswithrarecancers.
Potential Translational Research Consortia
Asthetranslationalresearchprocessevolves,anadditionallevelofcoordinationaroundorgan-specificdiseasesitesmaybebeneficialinenhancingsynergyandreducingredundancies.TheTRWGthereforerecommendsthattheAdvisoryCommitteeevaluatethebenefitsofestablishingorgan-specific,multi-institutional,multidisciplinary,multiprojectconsortiaintegratingallaspectsofearlytranslationalresearchacrosstheTRWGdevelopmentalpathways.Theseconsortiaareenvisionedtoincludethefollowingelements:
• Significanttranslationalandclinicalresearchexperienceintherelevantorgansystem
• Linkagetorelevantdiscoverylaboratoriesforidentificationofnewapproaches
• ExpertiseinthetechnologiesrequiredfortherelevantTRWGdevelopmentalpathways
• Accesstocross-cuttingtechnologiessuchasimaging,animalmodels,high-throughputscreening,andassayvalidation
• Experiencewithmolecularmechanismsknowntoberelevanttotheorgansystem
• Accesstosignificantnumbersoftissuesamplesandexpertiseinthestandardizedcollection,storage,andannotationofrelevantbiospecimens
• Accesstotoxicology,pharmacology,andmanufacturingfacilitiesandexpertise
• Experienceintheconductofearly-stage,tissue-drivenPhaseIandPhaseIItrialsinrelevantpatientpopulationsandaccesstothosepatientpopulations
• Integrationwiththelate-stageclinicaltrialsinfrastructureforrelevantpatientpopulations.
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Indeterminingwhethersuchconsortiawouldbevaluableandfeasible,theTRWGrecommendsthattheAdvisoryCommitteeconsideravarietyofmodels.Forexample,onemodelwouldbetoestablishspecificrequirementsandsupplementalfundinginordertointegrateexistingfundingprogramsandprojectsintoconsortia.Anothermodelwouldinvolvecreatinganewmulti-institutional,multidisciplinaryconsortiumfundingmechanismbyconsolidatingseveralcurrentfundingmechanisms,atleastinpart.
TheTRWGrecommendsthattheAdvisoryCommitteeaddressthebenefitsofcreatingforthecommoncancers(e.g.,breast,prostate,lung,colorectal)twoormoreconsortiafocusedonspecificaspectsofthedisease(e.g.,therapyversusprevention)andalsoidentifyorgansystemsthatmightbeespeciallyappropriateforpilotingofsuchanapproach(e.g.,rarecancers).Inaddition,theTRWGsuggeststhattherewouldbesubstantialbenefitinconfiguringtheseconsortiainamatrixedmanner,notjustfororgansbutalsoforcross-cuttingthemes,suchasmolecularmechanismsorspecifictechnologies(e.g.,imaging,biospecimens,mousemodels,moleculardiagnostics)thatwouldinteractwiththeorgan-specificconsortia.Finally,theCommitteeshoulddeterminewhetherseedgrantswouldbebeneficialinencouragingtheextramuralcommunitytodevelopapproachesforbuildingsuchconsortia.
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Initiative A2: Designate a specific portion of the National Cancer Institute budget for early translational research.
Rationale
Currently,theNCI“translationalresearchbudget”isnotwelldefined.Anintegratedbudgetcomprisingidentifiabletranslationalresearchcomponents(i.e.,intra-andextramuralresearchinfrastructures,projects,personnel,etc.)andtheirmissionsdoesnotexist.AlthoughcertainNCIprogramsareclearlytranslational,identifyingall“translationalresearchawards”andunderstandingtheircontributiontothetranslationalresearchbudgetcurrentlyrequiresthedevelopmentofadhocinclusion/exclusioncriteriaandlabor-intensiveportfolioanalysesofindividualtranslationalresearchawards.Moreover,notargethasbeenestablishedfortheportionoftheNCIbudgetthatshouldbedevotedtotranslationalresearch.Thus,evenifthetotaltranslationalresearchbudgetwereknownwithaccuracy,itwouldstillbetheresultofalargenumberofindividualdecisionsasopposedtoacoordinatedprocesstoachieveanagreed-uponbudgetallocation.
TheportfolioanalysiscommissionedbytheTRWG(seeAppendixD)revealedthathalfoftheresearchidentifiedastranslationalwasfundedthroughinvestigator-initiatedR01andP01awards($662Mof$1.33B,or49.8%).3Giventhisprominenceofunsolicitedinvestigator-initiatedresearchwithinNCI’stranslationalresearchportfolio,withoutabudgettargettheactualamountoftranslationalresearchfundingcouldvarywidelyovertimedependinguponthefortunesofindividualproposalswithintheNIH-widepeerreviewsystem.
DesignatingaspecificportionoftheNCIbudgetfortranslationalresearchwillhavetwocriticalbenefits.ThefirstisthatNCIwillbeabletomanageitsinvestmentintranslationalresearchinacoordinatedfashion,facilitatinglong-termplanningandallowingprioritizationamongprogramsandapproaches.ThesecondbenefitisthatadesignatedbudgettargetwilldemonstrateNCI’srecognitionofandcommitmenttotheimportanceoftranslationalresearchthatisessentialtoachieveitscoremissionofimprovingthehealthofpatientsandthepublic.Moreover,achievingconsensusonadesignatedbudgettargetisavitalcomplementtothecreationofacoordinatedmanagementstructurefortranslationalresearchacrossNCI.ItisalsoinkeepingwiththeNIHDirector’scommitmenttodevoteapproximately35%oftheoverallNIHbudgettotranslationalresearch.4
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
TheAdvisoryCommittee(seeCoordinatedManagementInitiativeA1)willberesponsibleforrecommendingthedesiredpercentagetargetforNCI’sannualspendingontranslationalresearch.BasedontheTRWGtranslationalresearchportfolioanalysis(seeAppendixD),itappearsthatapproximately30%ofthetotalNCIbudget($1.33Brelativetoatotalof$4.4B)wasdevotedtotranslationalresearchinFY04.Althoughamoredetailedassessmentofasubsetoftheawardsindicatedthatthisnumbermaybehighbyasmuchas20-40%,itisreasonabletoassumethatcurrenttranslationalresearchfundingisintherangeof20-30%ofthetotalNCIbudget.Therefore,theTRWGrecommendsthattheinitialtargetbeinthe25%-35%range,whichisinlinewithDr.Zerhouni’srecommendation.TheTranslationalResearchOperationsCommitteeandtheAdvisoryCommitteewillusethisbudgettargettomanagetranslationalresearchacrossNCI,whiletheOfficeoftheDirectorwillusethebudgettargetasacomponentinmanagingNCI-wideresearchfunding.
Thetranslationalresearchbudgettargetwillbeexpectedtoencompassfourcomponents.Thefirstisthesolicited(i.e.,RFA/PA-directed)programsalreadyidentifiedastranslationalintheportfolioanalysis.Theseprogramsprovidecriticalinfrastructures,projects,andpersonneltoadvancetranslationalresearch.Thesecondistheunsolicited,investigator-
3 AlthoughtheportfolioanalysisdidnotassessfundingbyindividualProgramAnnouncementsorRequestsforApplication,itislikelythatthevastmajorityoftheR01andP01awardsidentifiedastranslationalareinvestigator-initiated.WhenfundingmechanismssuchasK-seriescareerdevelopmentawards,R37MethodtoExtendResearchinTime(MERIT)awards,andSmallBusinessInnovationResearch/SmallBusinessTechnologyTransferResearchawardsareaddedtotheR01andP01awards,nearly60%oftheidentifiedtranslationalresearchoccursthroughinvestigator-initiatedmechanismsnotnecessarilyspecificallydesignedbyNCItofostertranslation.
4 NIH at the Crossroads: Myths, Realities and Strategies for the Future.
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initiatedawardsidentifiedastranslationalbythenewcodingsystem(seeCoordinatedManagementInitiativeA3).ThethirdistheawardsresultingfromthenewsolicitedfundingprogramsproposedbytheTRWG(seeTailoredFundingProgramsInitiativesB3andB4).ThefourthistheoperationalexpensesassociatedwithimplementingandsustainingtheTRWGinitiatives.
Onceacompletepictureoftranslationalresearchfundingisobtainedbasedonthenewcodingsystem,theTranslationalResearchOperationsCommitteewillcomparethebudgettarget,onanannualbasis,withtheactualtranslationalresearchfundingactivitythroughbothsolicitedandinvestigator-initiatedawards.Ifthetargetfundinglevelisnotbeingachieved,fundingprioritieswillbeadjustedand/ornewdirectedprogramscreatedtobringactualfundinginlinewiththetarget.
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Initiative A3: Develop a set of award codes that accurately capture the nature and scope of the early translational research portfolio.
Rationale
Currently,thereisnosetofNCI-specificawardcodesthataccuratelyandexplicitlycharacterizestranslationalresearch,makingitnearlyimpossibletodeterminethenatureandscopeofNCItranslationalresearchfunding.Translationalresearchisnotspecificallyidentifiedbyanyofthecodesappliedtogrants,suchastheCommonScientificOutline(CSO),5SpecialInterestCategory,orNIHClinicalAspect(NIHCA)6codes,althoughtranslationalactivitieswouldclearlybeincluded,alongwithothertypesofresearch,incertaincategories.Therefore,inorderfortheTRWGtocharacterizetheNCItranslationalresearchportfolio,anadhoccodingsystemhadtobeemployed(seeAppendixD).Thiswasnotonlylabor-intensive,butitproducedresultsthatareopentocriticismbecauseoftheirdependenceonadhocinclusion/exclusioncriteriaregardingthetranslationalnatureofvariousprojectsandinfrastructurecomponents.
Managingtranslationalresearchmoreeffectivelyinthefuturewillrequirealogisticallystraightforwardandpreciselydefinedmethodforcodingawardsastranslational.Aunifiedsetofcodeswillhaveanumberofadvantages.ItwillenhanceunderstandingofNCI’soverallinvestmentintranslationalresearchandhelptoidentifygapsandopportunitiesinamoretimelyandeffectivemanner.ItwillalsoenableNCIstaff,leadership,andadvisorycommitteestobettermonitorthenatureandscopeofNCI’stranslationalresearchportfolioovertime.Andfinally,theestablishmentofmeaningfulawardcodeswillallowNCItobettercommunicatetranslationalresearchactivities,opportunities,andprogresstothepublic.Thisisessentialtobuildandsustainthepublic’scommitmenttoandparticipationintranslationalresearch.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
TheTranslationalResearchSupportOffice,underguidancefromtheTranslationalResearchOperationsCommittee,andinassociationwiththeResearchAnalysisandEvaluationBranch(RAEB),willdevelopanewsetofcodes,basedonthesixTRWGdevelopmentalpathways,thatoperationalizetheTRWGfunctionaldefinitionofearlytranslationalresearch.ThesenewcodeswillbeincorporatedintotheexistingNCIcodingsystemoperatedbyRAEB.
Integration with Current NCI Coding System
Currently,codingofallNCIawardsisperformedbyRAEBintheDivisionofExtramuralActivities,whichhasalargecodinggroupofprofessionalindexers.Thenewtranslationalresearchcodeswillbeincorporatedintothisestablishedsysteminthefollowingmanner.First,anawardwillbeclassifiedas“translational,”basedonitsrelevancetooneormoreoftheTRWGdevelopmentalpathways.Thedegreeoftranslationalrelevance(e.g.,25%,50%,75%,or100%)willalsobecoded.Onceatranslationalresearchcodehasbeenapplied,anadditionalgroupofcodeswillbeconsideredtofurthercharacterizetheexactnatureofthetranslationalresearchactivity(seebelow).Asimilarapproachtodetailedcodingisbeingemployedfortrans-NIHAIDS-relatedandnanotechnology-relatedresearch,whichmayserveasusefulmodels.Theimplementationofthenewtranslationalresearchcodeswillalsobecoordinated,asappropriate,withthenewportfolioanalysistoolsbeinginvestigatedbytheNIHOfficeofPortfolioAnalysisandStrategicInitiatives.
5 TheCommonScientificOutlineisaclassificationsystemthatdividescancerresearchintosevencategories:Biology;Etiology;Prevention;EarlyDetection,DiagnosisandPrognosis;Treatment;CancerControl,SurvivorshipandOutcomesResearch;andScientificModelSystems.Fullinfor-mationisavailableat:http://researchportfolio.cancer.gov/crp/cso.jsp.
6 NIHCAcodesarequartile-basedmeasures,assignedbyNCI’sResearchAnalysisandEvaluationBranch,oftherelevanceofprojectstotheNIHdefinitionofclinicalresearch.NIHdefineshumanclinicalresearchasfollows:1)Patient-orientedresearch—researchconductedwithhumansubjects(oronmaterialofhumanoriginsuchastissues,specimens,andcognitivephenomena)forwhichaninvestigator(orcolleague)directlyinteractswithhumansubjects.Excludedfromthisdefinitionarein vitrostudiesthatutilizehumantissuesthatcannotbelinkedtoalivingindi-vidual.Patient-orientedresearchincludes:a)mechanismsofhumandisease,b)therapeuticinterventions,c)clinicaltrials,ord)developmentofnewtechnologies.2)Epidemiologicandbehavioralstudies.3)Outcomesresearchandhealthservicesresearch.
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Coordination with Other Organizations
Indevelopingthenewcodes,theTranslationalResearchSupportOfficewillseekinputfromotherFederalagenciesthathavedevelopedtheirowncodingandtrackingsystems.Forexample,theDepartmentofDefense(DOD)hasworkedtogenerateataxonomysystemtocodeandtrackallfundedresearchfromtheinitialstagesuptopublicdelivery.Thesystemisnowbeingusedforportfolioanalysisandmonitoring,reportingof“success,”andongoingtrackingofprojects.AlthoughasystemofthistypemightbetoocomprehensivetobeimplementedthroughoutNCI,theDODhasdevelopedsomebestpracticesthatcouldproveuseful.TheSupportOfficewillalsoworkwiththeFoodandDrugAdministrationtoensureconsistencybetweentheeffortsofthesetwoagenciesandtoadoptcommonlanguageandclassificationsystems.
Coding Categories
Thenewcodeswillincorporatearangeofcategoriesrelatedtotranslationalresearch.TheRAEBalreadycodesgrantsbasedonorgansiteandtargetpopulations(rarecancers,pediatrics,minorities,underservedpopulations,etc.).Additionalcategoriesspecificallyrelevanttotranslationalresearchmightincludethefollowing:
• Mechanismofcancerdevelopment
Tissue/cellularlevel(e.g.,apoptosis,proliferation,angiogenesis)
Molecularlevel(e.g.,p53alterations,APCalterations,Her-2alterations)
PrimaryTRWGdevelopmentalpathway
Agent(drugorbiologic)
Immuneresponsemodifier
Biomarkerriskassessmentdevice
Imagingriskassessmentdevice
Interventivedevice
Lifestyleintervention
• RegionoftherelevantTRWGdevelopmentalpathway
Earlydevelopment/testing(targetvalidation,assaydevelopment,prototypedevelopment,etc.)
Optimization/validation
Preclinicaldevelopment(process/devicedevelopment,pharmacology,toxicology,manufacturing,etc.)
Early-stagehumanstudies
• Population
Averagerisk/unscreened
Elevatedrisk
Localdisease
Regionaldisease
Advanceddisease
Palliative.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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TRWGrepresentatives,NCIprogramstaff,TranslationalResearchSupportOfficestaff,andrepresentativesfromtheNCICenterforBioinformatics(NCICB),RAEB,andOfficeofSciencePlanningandAssessmentwillbeconvenedtodefinethecodesanddeterminehowtheycanbemostefficientlyandrapidlyincorporatedintothecodingsystem.ThenewcodeswillbeexpressedusingenterprisevocabulariesandCommonDataElementsdevelopedbyNCICB.
Coding of Awards
Oncethenewtranslationalresearchcodesareincorporatedintothecodingsystem,RAEBstaffwillcodeallnewlyfundedawardsbasedonthosecodes.Thiswillensurethatcodingisconsistentlyandobjectivelyappliedacrossalltranslationalresearchprojects.Itcurrentlyisnotpossibletocodeindividualsubprojectsforgrantswithmultiplecomponents(e.g.,SpecializedProgramsofResearchExcellence,P01s),althoughNCIandNIHareactivelyworkingtoincorporatesuchcapability.Ascodingofsubprojectsisessentialforaccurateportfolioanalysis,incorporatingsuchcapabilityshouldbeahighpriorityforbothNCIandNIH.Untilcodingofsubprojectsisimplementedcodingwillbeappliedtotheparentgrantonly,althoughallrelevantcodeswillbeincludedfromthesubprojects.OncecodinghasbeenassignedbyRAEB,itwillbeforwardedtotherelevantprogramofficerforconcurrencethatthecodeshavebeenappliedcorrectly.InordertogainacompletepictureoftheNCItranslationalresearchportfolioinatimelymanner,RAEBwillbeaskedtoassigntranslationalresearchcodesretrospectivelytoallactiveawardssoonafterthecodeshavebeenimplementedfornewawards.
Oncethenewcodingsystemisinplace,theTranslationalResearchOperationsCommitteewillevaluatetheoptionofinvestigator-assignedcodesthatarethenconfirmedduringpeerreviewandbyprogramandRAEBstaff.Iffeasible,theTRWGconsidersthislatteroptiontobehighlypreferable,asitwouldencourageamorecomprehensiveunderstandingonthepartofinvestigatorsoftheroleoftheirindividualresearchprojectstotheoveralltranslationalresearchprocess.
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Initiative A4: Establish a distinctive prioritization process for early translational research.
Rationale
Infundingdiscoveryresearch,NCI’sprimaryobjectiveistoenablequalifiedresearcherstofreelyexplorenewideasinfundamentalcancerscienceandpursuenewlinesofinquiryinwhateverdirectionsseemmostpromising.Infundingtranslationalresearch,ontheotherhand,NCI’sobligationistodeployitsscarceresourcessoastomaximizetheeffectiveness,speed,andefficiencywithwhichpromisingnewinsightsfromdiscoveryresearcharetransformedintotangibleproducts,7interventions,orlifestylealterationsthatcanimpactpatientcareorpublichealth.
Mechanismsforallocatingresourcesshouldbetailoredtotherespectivecharacteristicsofthesedifferenttypesofresearch.Fordiscoveryresearch,selectionmechanismsfocusonidentifyingthebestscientificideasproposedbyinvestigatorsqualifiedtopursuethem.Fortranslationalresearch,selectionmechanismsneedtoconsidernotonlythestrengthofthescientifichypothesis,butalsoidentifyconceptsespeciallyripefordevelopmentandtargetedatimportantunmetclinicalorpublichealthneedsunlikelytobeadvancedbyindustry.
Existingapproachestoselectionofresearchprojectsforfundingevolvedprimarilytosupportdiscoveryresearch.AstranslationalresearchisappreciatedasadistinctpartofNCI’sresearchportfolio,itisimportantthatappropriateselectionmechanismsbedevelopedtooptimizethatportionofourNation’sinvestmentincancerresearchaswell.Bycreatingaprioritizationprocessdistinctivetotranslationalresearch,itwillbepossibletoidentifyandprioritizeemergingtranslationalresearchconceptsandopportunitiesandensurethattheyareadvancedviaappropriateNCItranslationalresearchsupportmechanisms,withoutcompromisingthefunctionofexistingselectionprocessesandfundingtailoredtothedifferentneedsofdiscoveryresearch.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Theintentoftheprioritizationprocesswillbetoidentify,onanannualbasis,asmallnumberofspecificclinicalorproductdevelopmentgoalstobedesignatedasprioritiesbasedontheirripenessfordevelopmentandtheirpotentialclinicalsignificancefordefinedpatientsorpopulations.ThisnewprioritizationprocesswillbemanagedbyaPrioritizationWorkingGroupoftheAdvisoryCommittee(seeCoordinatedManagementInitiativeA1,page14,andFigure3).
Prioritization Working Group
Membership. ThePrioritizationWorkingGroupwillinclude15-20members,drawninpartfrommembersoftheparentAdvisoryCommitteeandinpartfromthelargercancerresearchcommunity.Membershipwillencompassarangeofkeystakeholders,including:
• Extramuraltranslationalresearchers,aswellasdiscovery,clinical,andpopulationresearchersexperiencedintheconductoftranslationalresearch
� “Products”includesneworrepurposeddrugs,biologics,devices,andothertangibleproductsthatcanbeusedfortherapeutic,diagnostic,prog-nostic,preventive,orpopulationriskassessmentpurposes.
Figure 3. Relationship of Prioritization Working Group to Coordinated NCI Organizational Structure
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• NCIprogramandintramuralresearchstaffexperiencedintheconductorcoordinationoftranslationalresearch
• Patientadvocates
• Nonacademichealthprofessionals
• Representativesfromafoundationactiveintranslationalresearchfunding
• Representativesfromindustry.
Inadditiontorepresentingthesestakeholdergroups,thePrioritizationWorkingGroupwillincludeexpertiseacrossthefollowingdomains:
• Diseasesites
• Mechanismsofcancerdevelopment
• TRWGdevelopmentalpathwaystoclinicalgoals
• Prevention
• Therapy
• Populationsciences
• Rarecancers
• Minority/underservedpopulations.
TopromotedynamismandadaptabilityoftheprioritizationprocessandensurethattheWorkingGroupiscontinuallyrefreshedwithnewperspectives,anewWorkingGroupwillbeformedeachyearwith30-50%newmembers.NoindividualwillserveonmorethanthreesuccessiveWorkingGroups.
Responsibilities. EachyearthePrioritizationWorkingGroupwillhavethefollowingresponsibilities,whichareexplainedingreaterdetailbelow.
1. Identifytranslationalresearchopportunitiesthatwarrantthehighestpriorityforadvancement.
2. IdentifygapsintheNCItranslationalresearchportfolio(i.e.,infrastructures,projects,personnel,resources)relativetotheseopportunities.
3. Recommendasubsetofthesehigh-priorityopportunitiesforSpecialTranslationalResearchAccelerationProjectfundingsolicitations(seeTailoredFundingProgramsInitiativeB3).
4. Issueareporttothecommunityontheidentifiedpriorities.
Prioritization of Opportunities
EachyearthePrioritizationWorkingGroupwillusethesix-stepprocessoutlinedbelowtoidentifythemostimportanttranslationalresearchopportunitiesforthatyear.Allofthesestepswillbesupported,facilitated,andimplementedthroughtheTranslationalResearchSupportOfficewiththeassistanceofotherNCIstaffand/orcontractors.
Information Gathering. ThePrioritizationWorkingGroup,withtheassistanceoftheSupportOffice,willsystematicallygather,review,andanalyzeinformationfromthepublishedliterature,includingreviewsandstate-of-the-sciencereports.ThegoalwillbetoidentifyconceptsthatpotentiallywarrantafocusedefforttoadvancethemdowntherelevantTRWGdevelopmentalpathway.
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ThePrioritizationWorkingGroupwillalsoconvene,asneeded,“TranslationalNeedsandOpportunities”symposiatoobtainexpertinputfromdiscovery,translational,andclinicalresearchers;manufacturingandregulatoryspecialists;managementexperts;industryrepresentatives;patientadvocates;andNCIprogramandintramuralresearchstaff.ThesesymposiawillbeorganizedbytheSupportOfficeandconductedasfocusedsessionsduringexistingprofessionalsociety,foundation,oradvocacygroupmeetings,and/oraspartofexistingprogrammeetings(e.g.,SpecializedProgramsofResearchExcellence,EarlyDetectionResearchNetwork)or“state-of-the-science”meetingsconductedbythedisease-specificScientificSteeringCommitteesformedaspartoftheClinicalTrialsWorkingGroupReportimplementation.
IfdeemedappropriatebythePrioritizationWorkingGroup(ortheparentAdvisoryCommittee),theSupportOfficewillconvenetargetedsubgroupsofkeyinvestigatorsandNCIprogramstafftoprovideneededinput.Thefocusofsuchsubgroupsmaybeorgan/diseasesystems(e.g.,breastcancer,leukemia/lymphoma),TRWGdevelopmentalpathways(e.g.,immuneresponsemodifiers,imaging),mechanismsofcancerdevelopmentorprogression(e.g.,proteinkinases,angiogenesis),orotherorganizingprinciples.Inparticular,theTRWGrecommendsthatsuchsubgroupsbeconvenedtoprovideinputonprioritiesforrarecancers,minority/underservedpopulations,andlifestyleinterventions.
Solicitation of Ideas. ThePrioritizationWorkingGroupwill,throughtheSupportOffice,issueaRequestforInformation(RFI)solicitingideasforimportanttranslationalresearchopportunitiesthatareripefordevelopment.TheRFIwillincludeasubmissiontemplatespecifyingthefollowingkeyelementsthatmustbeaddressedinorderforasubmittedconcepttobeevaluatedbythePrioritizationWorkingGroup:
• Keyresultsofdiscoveryresearchthatsupporttheopportunityproposed
• Keyfactorssupportingthetechnicalfeasibilityofafocuseddevelopmenteffort
• Importanceofclinicalorpublichealthneed
• Likelihoodthattheneedwillbemet,ortheopportunityadvanced,byprivateindustrywithoutNCIinvolvement.
Conceptsmaybesubmittedbytheresearchandadvocacycommunitiesatlarge,byadhocgroupsfocusedontranslationalresearch,orbyanyotherintra-orextramuralsource.Allconceptssubmittedwillbesubjecttoacommonreviewprocess.
Analysis of Input. Basedontheinformationgatheredfromtheliterature,theoutputoftheTranslationalNeedsandOpportunitiessymposia,andtheconceptsproposedinresponsetotheRFI,theSupportOfficewillpreparebriefconceptpackagesforthoseopportunitiesthathavethefollowingattributes:
• Astrongandvalidatedbodyofknowledgesupportingthepotentialofthediscoverytoleadtomeaningfulimpactoncancerprevention,detection,diagnosis,ortherapy
• Afeasibleseriesofstepsforadvancingthediscoveryintoearlyhumantesting
• Ademonstratedclinicalorpopulationhealthneedthatisnotadequatelyaddressedbyeitherexistingapproachesorthosealreadyindevelopment.
ConceptpackagessummarizingtheinformationsupportingeachoftheseattributeswillbepresentedtothePrioritizationWorkingGroupforreviewandprioritizationofupto10ofthemostpromisingtranslationalresearchopportunities.Inselectingpriorities,thePrioritizationWorkingGroupwillensurethatappropriateemphasisisplacedontheneedsofpatientswithrarecancersandmedicallyunderservedpopulations.
Portfolio Analysis. Foreachselectedopportunity,theSupportOfficewillanalyzethecurrentNCIgrantportfoliotodeterminethescopeofongoingtranslationalactivityrelevanttothatopportunity.Thisanalysiswillidentifywhatadditionalresearchactivitiesarerequiredtocompleteafocused,coordinated,andfacilitatedtranslationalresearchefforttomovetheidentifiedconceptintoearlyhumantesting.Theportfolioanalysiswillalsoattempttoidentifyrelevantresearchunderwaywithfoundation,industry,orotherGovernmentagencysupport.ThiswillallowNCItoavoid
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duplicationofongoingeffortsandidentifyopportunitiesforsynergy.Basedonthisanalysis,thePrioritizationWorkingGroupwillselectthefivehighestpriorityopportunities.
Public Comment. ThePrioritizationWorkingGroupwillpublishtheconceptpackagesforthefivemostpromisingopportunities,presentthemfordiscussionataspecialannualTranslationalResearchNeedsandOpportunitiessymposiumreservedespeciallyforthispurpose,andsolicitpubliccommentmoregenerally.Allcommentsreceivedwillbeanalyzedandusedtorefineandfurtherprioritizetheselectedopportunities.
Selection of Prioritized Opportunities. Takingintoaccountalloftheinputreceivedandtheanalysisconductedaswellasitsowncollectiveknowledgeandexpertjudgment,thePrioritizationWorkingGroupwillrankordertheidentifiedopportunities.Inpreparingtheranking,thePrioritizationWorkingGroupwillensurethatappropriateemphasisisplacedontheneedsofpatientswithrarecancersandmedicallyunderservedpopulations.ThePrioritizationWorkingGroupagainwillselecttwoorthreeoftheopportunitiesassubjectsforSTRAPsolicitations(seeTailoredFundingProgramsInitiativeB3).TheprioritizedopportunitiesplustherecommendationsforSTRAPsolicitationswillbeforwardedtotheAdvisoryCommitteeforreviewandapproval.TheAdvisoryCommitteewillthenforwardtheprioritiesandSTRAPrecommendationsthattheyapprovetotheExecutiveCommitteeandtheBoardofScientificAdvisorsforfinalreviewandapproval.Uponfinalapproval,theprioritieswillbepublishedandusedtoformthebasisforSTRAPsolicitationsandtoguidetranslationalresearchacrossNCI.
Application of Priorities Across NCI
TheTranslationalResearchOperationsCommitteewilldeveloppoliciesandproceduresforintegratingthedesignatedpriorities,asappropriate,intoSpecialEmphasisPanelreviewcriteriaandintofundingdecisionsbyprogramstafffortheoverallNCItranslationalresearchportfolio,includingP50,U-series,P01,andR01awards,aswellasforstimulatingthecreationofnewinitiativesbyprogramstaffonspecificpriorities.TheOperationsCommitteewillalsoinformotherstandingcommittees,suchastheInvestigationalDrugSteeringCommitteeandthedisease-specificScientificSteeringCommittees,abouttheidentifiedpriorities,sothattheycanbeincorporated,asappropriate,intotheirrespectiveactivities.
Annual Report
Followingcompletionofitsdeliberationsforthatyear,thePrioritizationWorkingGroupwillissueareportcoveringthefollowingtopics:
• DescriptionoftheWorkingGroup’sactivities
• Listofprioritizedopportunities,includingrationaleforselection
• Summaryofotheropportunitiesproposedbutnotselectedforprioritization
• SummaryofSTRAPsolicitationsproposed.
This Page Intentionally Left Blank.
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Tailored Funding Programs
Introduction
Fundingprogramstailoredtothedistinctiveneedsandcharacteristicsoftranslationalresearchareessentialtoadvancepromisingconceptstothepointofinitialtestingofaspecificdrug,biologic,device,procedure,orotherinterventionintheclinicorcommunity.However,themajorNCIfundingmechanisms,especiallyR01sandP01s,aredesignedprimarilytoenableresearcherstoexplorenewideasinfundamentalscienceandpursuenewlinesofinquiryinresponsetotheirresults.Whileidealfordiscoveryresearch,thesemechanismsarenotwellmatchedtothegoalsoftranslation.
Asaresult,severaltargetedfundingprogramshavebeendevelopedoverthelastseveralyears,especiallytheP50andvariousU-seriesprograms,toaddressthetranslationalresearchopportunitiesemergingfromrecentadvancesincancerbiology.Thefuturevitalityoftranslationalresearchdependsatleastinpartoncontinuedrefinementofthesecurrentprogramstoreflectevolvingbestpracticesinthemanagementoftranslationalresearch.Managementbestpracticesofparticularimportanceincludeaprojectplancoveringalltheactivitiesuptoandincludingearly-stageclinicaltrials,projectmilestoneswithassociateddatesandfundingrequirements,anddevelopment/commercializationstrategiesdescribinglikelyapproachesforlate-stagehumantestingandeventualcommercialization.
Inadditiontorefiningexistingprograms,NCI’stranslationalresearchportfolioshouldbeaugmentedbytwonewprogramsthatexemplifythesebestpracticesandaddressimportanttranslationalopportunitiesnotcapturedbyexistingefforts.Forsupportingemergingopportunitiesselectedbythenewprioritizationprocess(seeCoordinatedManagementInitiativeA4),anewtypeoffundingprogramisneededthatcanassembleanoptimalmixofresources,investigators,andinstitutionstoconductalarge,integrated,multidisciplinaryefforttoaccomplishaprioritizedtranslationalgoal.Inaddition,althoughNCIhasseveralprogramsthatencourageindustryinvolvement,itwouldbeadvantageoustodevelopanewprogramthatrequiresindustryresourceandcostsharing.Suchaprogramwouldincentivizeindustryinvolvementinprojectstheywouldnottakeforwardindependently.Andfinally,itisimportanttointegratesuccessful,milestone-drivenearlytranslationalresearchprojectsseamlesslywithNCI-fundeddevelopmentresourcesinordertopreventunnecessarydelaysinmovingprojectstowardhumantesting.
Toachievethedesiredimprovementsinfundingprogramstofacilitateandpromotetranslationalresearch,theTRWGproposesfiveinitiatives.
B1. Modify multiproject collaborative award guidelines, as appropriate, to facilitate early translational research.
B2. Improve processes and mechanisms for funding investigator-initiated early translational research.
B3. Establish a special translational research funding program to advance prioritized early translational research opportunities.
B4. Establish a funding program for early translational research that requires academic/industry collaboration involving resource sharing and/or co-funding.
B5. Integrate access to GMP/GLP manufacturing and other preclinical development services more effectively with milestone-driven early translational research projects.
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Initiative B1: Modify multiproject collaborative award guidelines, as appropriate, to facilitate early translational research.
Rationale
NCIhascreatedadiverseportfolioofProgramAnnouncement/RequestforApplication-directedtranslationalresearchfundingprogramsthatsupportmultiproject,collaborativeawards.Theseincludecenter/multiprojectawards(P50programs)andavarietyofcooperative-agreementbasedprograms(U01,U19,U24,andU54).Inaddition,usinganRFAapproach,NCIcanestablishP01programsspecificallyfocusedontranslationalresearch.Becauseofthedifferingcircumstancesunderwhichtheywerecreatedandthedifferentmodelsonwhichtheyarebased,theseprogramsutilizearangeofmanagementpractices,programguidelines,andreviewapproaches.
Throughitsdeliberations,theTRWGidentifiedanumberofmanagementbestpracticesthatifuniformlyincorporatedintoprogramguidelinesformultiprojectcollaborativeawardswouldfacilitatetranslationalprogress.Thepurposeoftheseproposedmodificationsisnottohomogenizealltranslationalresearchprogramsorforcethemintoacommonmodel.Rather,thegoalistoenhanceproductivityacrosstheenterprisebyconsistentlyimplementingbestpracticesformanagementelementssharedbyalltranslationalresearchprograms,whilemaintainingthevariationinresearchdesignandscientificapproachthatisessentialtoinnovationandproblemsolving.
Thesecommonmanagementelementsinclude:
• FocusresearchprojectsonaccomplishingspecificmilestonesalongtheTRWGdevelopmentalpathwaysinordertomovediscoveriesefficientlyforwardintohumantesting.
• Rewardprojectsthathaveadefineddevelopmentandcommercializationstrategy.
• Rewardinter-institutionalcollaborationandnetworkformation,includingwithindustry.
• Incentivizeparticipationbyincreasingbudgetaryauthorityandresponsibilityandrewardingsuccesswithgreaterfundingstability.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
GuidelinesfortheSpecializedCentersP50programs(e.g.,SPORE,ICMIC)8andcooperativeagreement-basedprograms(e.g.,EarlyDetectionResearchNetwork[EDRN],NetworkforTranslationalResearch:OpticalImaging[NTROI],NationalCooperativeDrugDiscoveryGroups[NCDDGs])9willbereviewedandmodifiedasdescribedbelow.SincetheseareNCI-specificprogramsreviewedbyNCI-charteredSpecialEmphasisPanels,theycanbeflexibleinincorporatingtranslationalresearchprinciplesintothedesignoftheirRFAsorPAsandtheirprogramguidelines.10Anynewtranslationalresearch-oriented,multiproject/collaborativeprograms,includingRFA-directedP01programs,willalsoincorporatetheseprinciples.
8 TheP50center/multiprojectawardsfundseveralindependentresearchprojectsandsupportingcores,organizedaroundacommonthemesuchasanorgansite.Thecenterprincipalinvestigatorcoordinatestheoveralleffortandhasdiscretiontoreallocatefundsamongprojectsandtoter-minateprojectsasnecessary.Unlikecooperativeagreement-fundednetworks,thereisnoformalprogram-widegovernancestructureorSteeringCommittee.DiscretionaryfundsheldattheprogramlevelaredisbursedbytheNCIprogramofficerthroughasupplementprocess.
9 CooperativeagreementprogramssuchasEDRNandNTROIarestructuredsuchthateachawardactsasacomponentofacommonresearchnetwork.ThenetworkhasaSteeringCommitteeconsistingofawardprincipalinvestigatorsandNCIprogramofficersthatdirectsnetwork-wideresearchactivitiesanddisbursesfundsheldatthenetworklevel.Othercooperativeagreementprograms,suchasNCDDG,fundmultipleinter-relatedprojectswithineachawardbutdonotcoordinatetheawards.
10 AllguidelinechangeswillbesubjecttoNIH-widereview.P01guidelinechanges,especially,mayrequireNIH-wideinputtoensurethatmodifi-cationsremainwithintheboundariesoftheP01programprojectconcept.
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TheTranslationalResearchOperationsCommittee,withsupportfromtheTranslationalResearchSupportOffice,willreviewtheguidelinesofotherU-seriesprogramsidentifiedas“translational”butwhichcontributemodelsystems(e.g.,MouseModelsConsortium),coreresources(e.g.,CooperativeHumanTissueNetwork),orspecificservices(e.g.,PhaseI/IIconsortia)todeterminewhich,ifany,ofthetranslationalresearchprinciplesdelineatedbelowshouldbeincorporatedintotheirprogramguidelines.11
Incorporation of Milestones
TheguidelinesforP50andtranslationalU-seriesprograms,aswellasRFA-directedtranslationalP01programs,willbemodifiedtorequiretheinclusionofmilestonesinproposedprojectplans.Milestoneswillbedevelopedbytheinvestigatoronaproject-specificbasis,butwillbebasedonthestepsintheTRWGdevelopmentalpathways(seeAppendixCforpathways).
ForP50programs,eachindividualresearchprojectwillberequiredtoproposeasetofmilestonestobeachievedoverthe5-yeargrantperiod.Themilestoneswouldsetoutthestartingpointoftheproject,theprojectedpathwaystepsthatwouldbecompletedbytheendofthe5-yearfundingperiod,andspecificmilestonesthatwouldbereachedduringtheawardperiod,includingdatesbywhichsuchmilestonesareexpectedtobeachieved.Thereasonablenessoftheproposedmilestonesintermsofchartingefficient,timely,andyetrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.Eachresearchprojectproposedshouldhaveearlyhumantestingasthefinalmilestone.However,notallprojectswillbeabletomeetthatmilestonein5years.Therefore,proposingareasonablesetofinterimmilestoneswiththegoalofenteringhumantestinginasubsequentgrantperiodwillbeacceptableforcertainprojects.
Eachprojectwillbesubjecttorigorousformalreviewatthetimeofeachprojectedmilestone.Inprogramsthataregovernedbyaprogram-wideSteeringCommittee(e.g.,EDRN,CentersofCancerNanotechnologyExcellence[CCNE]),themilestonereviewwillbeperformedbytheSteeringCommittee.Inprogramswhereawardshaveexternaladvisorygroups(e.g.,manySPOREawards,someP01awards),theseadvisorybodieswillparticipateinmilestonereview.Resultsofthemilestonereviewwillbeusedbytheprincipalinvestigatortomakeadecisiononcontinuation,modification,orterminationofthespecificproject.Whenappropriate,milestonereviewwillbeintegratedwithreviewbytheRAID,RAPID,orDCIDEprograms(seeTailoredFundingProgramsInitiativeB5).Inaddition,wheneverprojectsreachthestageofPhaseIIclinicaltrialdesign,milestonereviewsanddesignactivitieswillbecoordinatedwiththeongoingclinicaltrialprioritizationeffortsofanyrelevantdisease-specificScientificSteeringCommitteesestablishedasaresultoftheClinicalTrialsWorkingGroupReportimplementation.
Annualprogressreportswillrequireanaccountofthestatusofproposedmilestones.Ifforagivenprojectamilestonehasnotbeenachievedbytheprojecteddate,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbeterminated.
Successinachievingtheproposedmilestonesandeffectiveactiontoterminateormodifyprojectsthatarenotachievingtheirmilestoneswillbekeyreviewcriteriaatthetimeofcompetitiverenewal.Movingexistingprojectsforwardaccordingtoamilestone-basedplanwillbemoreimportantincompetitiverenewalthangenerationofdataonwhichtobasenew,futureprojects.Fornetworkprograms,progressinachievingmilestoneswillbetakenintoaccountinevaluatingindividualawardswithinthenetworkforrenewal.ForP50andP01awards,successinachievingmilestonesthroughoutthevariousresearchprojectsandactingtomodifyorterminateunsuccessfulprojectswillbeacriticalelementatthetimeofcompetitiverenewaloftheentireaward.
Development/Commercialization Strategies
Becausetranslationalresearchprojectsareintendedtoresultindrugs,biologics,devices,procedures,orotherinterventionsthatultimatelybenefitpatients,guidelinesfortranslationalresearchP50,U-series,andRFA-directed
11 CertainclinicalresearchU-seriesprograms(e.g.,PhaseIU01trialists,AmericanCollegeofRadiologyImagingNetwork[ACRIN],thecoopera-tivegroups,andCommunityClinicalOncologyPrograms[CCOPs])arenotintendedtobecoveredbythisinitiative.
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P01programswillbemodified,asnecessary,toincludearequirementtopresentaproposeddevelopmentandcommercializationstrategyforeachprojectproposed.12ThestrategywilldescribenotonlytheenvisionedapproachforproceedingalongtherelevantTRWGdevelopmentalpathwayintoearlyhumantestingbutalsoananalysisoftherequirementsandpotentialoptionsforlater-stagehumanstudiesandeventualproductcommercializationand/ordisseminationtothelargercommunity.
Iftheultimategoalisacommercialproduct,whetherfortesting,therapy,orprevention,thestrategywillincludeadescriptionoftheoptimalstageforindustryhandoffandpotentialcommercializationpartners.Thestrategywillalsoincludeaplanforprotectingandlicensinginventionsanddescribeanylicenseormaterialtransferagreementsalreadyinplace.Thestrengthandfeasibilityofthedevelopmentstrategywillbeanimportantcriterionininitialreview,andprogresstowardestablishingtherelationshipsnecessarytoimplementthestrategywillbeanimportantcriterioninrecompetingreview.TheNCDDGprogramalreadyincludesguidelinesandreviewcriteriafordevelopmentplansthatmayserveasastartingpoint.
Promotion of Collaborations
SPOREguidelinescurrentlyencourageinterinstitutionalcollaborationsbothwithotherSPOREsandwithotherNCI/NIHprograms.Thiswillbestrengthenedbymakingevidenceofmeaningfulinterinstitutionalcollaborationanimportantelementinbothinitialandrecompetingreview.ComparablerequirementsforcollaborationwillbeincorporatedintoallnewandexistingP50andtranslationalRFA-directedP01programs.Becauseindustrycollaborationscanbecriticalfortheultimatevalueoftranslationalresearchforpatients,guidelineswillbemodifiedtoencourageindustrycollaborationsandrewardtheminreview.Suchcollaborationsmayincludeco-fundingofprojects,in-kindprovisionofmaterialsortechnicalassistance,industryadvisoryroles,orhandoffofprojectsreachingmaturity.Industrycollaborationswillnot,however,serveasapreconditionforawardorrenewal.
NetworkssupportedbycooperativeagreementssuchasEDRNandNTROIcurrentlyincentivizeandrewardcollaborationswithotheracademicinstitutionsandindustrybyprovidingcollaboratorswithassociatemembershipsandallocatingnetworkfundstofacilitatecollaborations.CollaborationswithindustryareexplicitlyincorporatedintoEDRNreviewcriteriaandencouragedbytheNCDDGprogram.SimilarincentivesandrewardsforinterinstitutionalandindustrycollaborationwillbeincorporatedintotheguidelinesofallothernewandexistingU-seriestranslationalresearchprograms.
NCItermsandconditionsofawardrequiresharingofresearchresources(e.g.,researchtools,celllines,modelsystems),andplanstoshareresourcesarerequiredandusedinreviewforallP50,U-series,andRFA/PA-directedprograms.However,giventheimportanceofcollaborationintranslationalresearch,guidelineswillbemodifiedtospecifynotonlythatplansarerequired,butalsothatsharingofresourcesduringtheawardperiodwillbeanimportantcriterionduringrecompetingreview.
Budgetary Flexibility
Maximizingthebenefitofmilestone-drivenprojectreviewswillrequirethatprincipalinvestigatorsand/orsteeringcommitteeshavetheabilitytoreallocateorredirectfundswhenprojectsarecompletedorterminatedearly.Thiscouldinvolveprovidingadditionalfundstoaccelerateexistingprojectsorprovidingfundsforthestartupofnewprojects.Suchbudgetaryflexibility,whichisalreadyincorporatedintoSPOREawardsandcertainU-seriesnetworkawards,willbeexpandedtoallP50,RFA-directedP01,andU-seriestranslationalresearchprograms.Effectiveuseofthisbudgetaryflexibilitytokeeptheoverallprogramontrackdespiteeventsinindividualprojectswillbeanimportantreviewcriterionforcompetingrenewals.Ifongoingpeerreviewofthesedecisionsiswarranted,externaladvisoryboardsassociatedwiththeprogramshouldbechargedwithprovidingthisservice.
12 Commercializationplanswillbetailoredtotheneedsoftheindividualapplication.Forexample,ifasetofprojectscombinetoproduceasingletranslationalproduct,orifanindividualprojectwithinatranslationalmechanismisnotintendedtoproduceaspecifictranslationalproduct,ap-plicantswillnotberequiredtoproposeadevelopmentplanforeachproject.
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Review Panels
P50,U-series,andRFA-directedP01applicationsarereviewedbySpecialEmphasisPanelsconvenedbyNCIratherthanthroughtheNIH-wideCenterforScientificReview.Forawardprogramsfocusedontranslationalresearch,andinlightoftheproposedguidelinechangesdiscussedabove,involvementbyindustryscientists,nonacademichealthprofessionals,programmanagersatfoundationsfundingcancerresearch,andpatientadvocates,inadditiontoacademictranslationalresearchersisespeciallyimportant.Asguidelinechangesareimplemented,therostersofthesepanels,includingtheP01DiscoveryandDevelopmentSpecialEmphasisPanel,willbeexaminedbytheDivisionofExtramuralActivitiesResearchProgramsReviewBranchtodeterminewhetheradditionalreviewersmaybeneeded.Shouldtheevaluationidentifypotentialgapsorlimitationsinrostermembership,theResearchProgramsReviewBranchwillcoordinatewiththeTranslationalResearchSupportOfficeandrelevantprogramstaffinidentifyingandrecruitingadditionalmembers.Astranslationalresearchprogramsbecomemorecollaborative—bothamongacademicresearchersandbetweenacademicandindustryresearchers—recruitingqualifiedreviewersfreeofconflictofinterestmayrequireafocusedandproactiveeffortonthepartofNCI.
Rolling Review
Oncemilestoneshavebeenincorporatedintoprojectplansasobjectivecriteriaforevaluatingthesuccessorproductivefailureoftranslationalresearchprograms,theTranslationalResearchOperationsCommitteewill,inconsultationwiththeDivisionofExtramuralActivities(DEA),considerwhethera3+3rollingreviewsystemforselectedawardsisfeasibleand,ifso,howitmightbestructured.13Suchareviewsystemwouldinvolveconductingafullprogramreview(comparabletoacompetitivereview)after3yearsofa5-yearaward,withoneoftworesults.Iftheawardisgoingwellandmeetingmostifnotallofitsprojectmilestones,theawardwouldberenewedforanother5yearswith,again,afullprogramreviewafter3years.Iftheawardhasexperienceddifficultyinmeetingmilestonesandredirectingprojectfunds,itwouldbesubjecttoterminationattheendoftheremaining2-yearperiodunlesssignificantpositiveprogressweremade.
13 AnysuchchangeswouldbesubjecttoNIH-widereview.
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Initiative B2: Improve processes and mechanisms for funding investigator-initiated early translational research.
Rationale
TheTRWGportfolioanalysisfoundthatmorethanhalfoftheidentifiedearlytranslationalresearchawardswerefundedthroughmechanismsdesignatedforunsolicited,investigator-initiatedresearch,predominantlyR01sandP01s(seeAppendixD).TheprogrammaticguidelinesforthesemechanismsaresetNIH-wide,andtheyweredevelopedprimarilyforthesupportofdiscoveryresearch.Asaresult,theydonotincorporateimportanttranslationalresearchconcepts,includingmilestones,collaboration,developmentplans,etc.Moreover,althoughseveraloncologystudysectionshavebeenrecentlyestablishedthatarefocusedontranslationalresearch,thereisstillaperceptionthattranslationallyorientedR01sandP01sfareworseinpeerreviewthandodiscovery-orientedproposals.
ImprovementsintheprocessforreviewandfundingoftranslationallyorientedR01andP01applications,asdistinctfromdiscovery-orientedapplications,arethusnecessarytoincentivizeinvestigatorstoproposesuchprojectsbyassuringthattheirapplicationswillbejudgedbyreviewcriteriatailoredtotranslationalresearch.SuchimprovementswillassistNIHinachievingthesecondcomponentofitsmission—“...applicationof(that)knowledgetoextendhealthylifeandreducetheburdensofillnessanddisability”14andareespeciallyimportantgiventheprominenceoftheResearchProjectGrant(RPG)poolintheoverallNCI,andNIH,fundingportfolio.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Translational Research Study Section Analysis
RecenteffortsbytheNIHCenterforScientificReview(CSR)andNCIresultedincreationoftheOncologicalSciencesIntegratedReviewGroup,whichincludessixstudysectionsspecificallyorientedtowardtranslationalresearch.Todeterminewhetherthesenewstudysectionsareprovidingadequateandequitablereviewoftranslationalresearchapplications,theTranslationalResearchSupportOfficewillcoordinatewiththeNCIDEAandCSRtoconductananalysisofcurrentstudysections.Theanalysiswillhavethreecomponents.Thefirstistoexaminewhetherthereareanygapsinstudysectioncoverageforspecificareasoftranslationalresearch(e.g.,immunotherapy,imaging,lifestyle).Thesecondistoevaluatereferralguidelinesforthestudysectionsandperceptionsofstudysectionmembersconcerningwhethertheyreceiveanappropriateportfolioofgrantstoreview.Thethirdistoexaminemembershiponthestudysectionstoidentifyanygapsinthetranslationalresearchexpertiserepresented.
Ifanygapsinstudysectioncoverageareidentified,theSupportOfficewillworkwithDEAandCSRstafftoexpandthemandateofexistingstudysectionsorsuggestthecreationofnewstudysectionstofillthosegaps.Ifdeficienciesinstudysectionoperationsareidentified,theSupportOfficewillcoordinatewithDEAandCSRtorefineproceduresandreferralguidelines.Wherethereappeartobegapsinreviewerexpertise,theSupportOfficewillidentifyadditionaltranslationalresearchersqualifiedforserviceonstudysections.Ascollaborationintranslationalresearchincreases,SupportOfficestaffwillcoordinatewithCSRtodevelopstrategiesforidentifyingandrecruitingqualifiedreviewerswhoarefreeofconflictsofinterest.TheSupportOfficewillalsoworkwithCSRtoencouragetheinvolvementofpatientadvocatesinstudysectionsorientedtowardtranslationalresearch.
ArelatedactivitywillbetoworkwiththeDEAResearchProgramsReviewBranchtoassessthereviewoftranslationalP01sthroughNCI-charteredSpecialEmphasisPanels.Thisassessmentwillinclude:a)determiningtheeffectivenessofthepilotsingle-tierP01structureasappliedtotranslationalP01applications;b)assessingthetreatmentofP01applicationsidentifiedas“translational”astheyareassignedtothefivestandingpanels(MolecularBiology;Cellularand
14 NationalInstitutesofHealth:http://www.nih.gov/about/index.html#mission.htm.
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TissueBiology;Prevention,Control,andPopulationSciences;DiscoveryandDevelopment;andClinicalStudies);andc)identifyingpotentialimprovementstotheP01reviewprocesswithintheboundariesoftheNCI-wideP01guidelines.
Exploration of Translational R-Series and P-Series Mechanisms
NIHhasadualmissionofscientificdiscoveryandtranslationaldevelopmenttobenefithumanhealth.R01andP01mechanisms,whichserveasthefoundationofNIH’sgrant-basedeffortstoachievethesegoals,aregovernedbyNIH-wideguidelinesthatarenotspecifictothetranslationalmission,nortotheneedsofanyindividualInstituteorCenter.However,becausethechallengesoftranslationalresearcharecriticallyimportanttoallNIHInstitutesandCenters,NIHshouldevaluatewhetheritsoverallgrantprogramproperlyincentivizesandsupportstranslationalresearch.
BecauseNCI’sperspectivesontranslationalresearchneedsandopportunitiesmaybesharedbyandusefultootherInstitutesandCenters,NCIwillpursueanNIH-wideinitiativetoexaminethevalueofcreatingdistinctiveR-seriesandP-seriesmechanismsforsupportingunsolicited,investigator-initiatedtranslationalresearch.Thesemechanismswouldincorporatecharacteristicsdesirablefortranslationalresearch(e.g.,milestone-basedreview,team-basedscience,projectmanagement,device/interventiondevelopment)andensurethatreviewoftranslationalresearchproposalsreflectsthesecriteria.
MembersoftheTranslationalResearchOperationsCommittee,withsupportoftheTranslationalResearchSupportOffice,willbeginadialoguewithotherNIHInstitutesandCentersconcerningthepotentialvalueofnewR-seriesandP-seriesmechanismsfocusedontheneedsoftranslationalasopposedtodiscoveryresearch.OneopportunitywouldbetoworkwiththeNIHOfficeoftheDirector/OfficeofPortfolioAnalysisandStrategicInitiativestodevelopaRoadmapinitiative.
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Initiative B3: Establish a special translational research funding program to advance prioritized early translational research opportunities.
Rationale
Theprimaryobjectiveofearlytranslationalresearchistoadvancepromisingconceptseithertoinitialtestingintheclinicorpopulationortothepointwhereresultsindicatethatanalternateapproachshouldbepursued.Inmanysituations,existingfundingprograms,whichadvanceknowledgeincrementallybysupportingportionsofadevelopmentalpathway,likelyconstituteanoptimaluseofresources.However,incertaininstances,opportunitiesarisethatareespeciallypromising,bothbecauseoftheirapparentreadinessfordevelopmentfromascientificandtechnicalperspectiveandbecauseoftheirpotentialclinicaland/orpublichealthimpact.ThenewtranslationalresearchprioritizationprocessproposedbytheTRWG(seeCoordinatedManagementInitiativeA4)isintendedtoidentifyjustsuchopportunities,especiallythosethatareunlikelytobepursuedbyprivateindustrybecausetheymaynotbejustifiableonbusinessgrounds.Thisisespeciallylikelytobetrueofopportunitiesrelatedtorarecancers,minority/underservedpopulations,immunotherapies,andlifestylealterations.
Whileitmightbepossibletoadvancetheseprioritizedopportunitiesthroughexistingprograms,progressalongaspecificdevelopmentalpathwayislikelytobeslowifdifferentstepsaresupportedviamultiple,uncoordinatedfundingvehiclessubjecttoseparatepeerreview.Evenunderidealcircumstances,suchfragmentedfundingwillimposeburdensoftime,logisticalcomplexity,andcostthatcanimpedeprogress.Accordingly,NCIshoulddevelopaninnovativefundingprogramthatisdesignedtoadvancecertainprioritizedearlytranslationalresearchopportunitiesefficientlyalongtheappropriateTRWGdevelopmentalpathwayinacoordinatedandhighlyfacilitatedfashion.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
NCIwillestablishanewfundingprogramentitledtheSpecialTranslationalResearchAccelerationProject(STRAP)program.Thisprogramwillbedesignedtofundtheadvancementofspecificopportunities,identifiedbythenewtranslationalresearchprioritizationprocess,alongoneoftheTRWGdevelopmentalpathwaysthroughearlyhumantestingofaspecificdrug,biologic,diagnostic/screeningtest,orothertherapeutic,diagnostic,orpreventiveintervention.Thisprogramisnotintendedtodevelopnewscientificknowledge,researchmethodologies,orinfrastructureexceptwhennecessaryforandlinkedtothedevelopmentofspecificproductsorinterventions.
STRAPawardswillsupportanintegratedresearchanddevelopmentprogramdesignedtoachieveaspecificclinicalorproductdevelopmentgoal.TheinitiationofaSTRAPcanoccuratavarietyofpointsatthebeginningof,orearlyin,aTRWGdevelopmentalpathway.However,theprojectplanandproposedbudgetwillextendthroughtheendofthedevelopmentpathway(i.e.,tothepointofearlyhumantesting)andencompassasubstantialportionofthepathway.STRAPawardsareintendedtosupportalargerscopeofintegratedactivityandhaveahigherdegreeofNCI-facilitationthanwouldbefeasibleunderanyofthefundingprogramscurrentlyinexistence.
ThesizeanddurationofaSTRAPawardwillbedeterminedonaproject-specificbasis,vianegotiationbetweenNCIandtheprincipalinvestigators,inlightoftheneedsoftheparticularresearchanddevelopmentplan.Itisunderstoodthatincertaincases,thegoalsofaSTRAPmayentailaneffortlastingmorethan5years.
Structure
Bydefinition,aSTRAPawardisintendedtosupportatranslationalresearchopportunitythathasbeenprioritizedbecauseofacombinationofscientificcredibility,technicalfeasibility,clinicalorpublichealthimpact,andthelikelihoodthattheopportunitywillnotbepursuedbyanotherfundingagency(i.e.,privateindustry,foundation,othergovernmentalagency).
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Inmanycases,thescientificcredibilityandtechnicalfeasibilityofaconceptwillbebasedontheresultsofoneormoreexistingresearcheffortsalongtherelevantTRWGdevelopmentalpathway.Insuchsituations,itmaybeappropriateforNCItoimplementaSTRAPbyintegratingexistingawardsandmakingnewawardstocoverthemissingcomponentsofthedevelopmentalpathway.
Inothersituations,asubstantiallynewscopeofworkmaybeoptimalforachievingtheobjectivesofaSTRAP.Accordingly,theSTRAPprogramwillalsoprovideforentirelynewawardscoveringtheentiredevelopmentalpathwayforaconceptjustemergingfromdiscoveryresearchthatisdeemedsufficientlycompellinganditsdevelopmentpathconceptualizedwithsufficientclaritytojustifyafocused,prioritizeddevelopmenteffort.
Becauseofthediverserequirementsandmultidisciplinarycharacterofthedevelopmentalpathways,STRAPawardsmayuseanyorallofthefollowingstrategieswhenevertheywillfacilitatetimelyandefficientachievementofthegoalsoftheSTRAP:
• Participationofmultiple,collaboratingprincipalinvestigators,includinginvestigatorsfromtheNCIintramuralresearchprogram
• Collaborationofmultipleacademicinstitutions
• Collaborationwithindustrytoaccesscomplementaryhuman,infrastructure,and/orfinancialresources
• Contractswiththeprivatesectorforappropriateactivities(standardanalyses,manufacturing,etc.)
• Collaborationandcoordinationwithexistingfoundation-supportedeffortsrelevanttothegoalsoftheSTRAP.
Funding
Approximately$10millionwillbeallocatedtonewSTRAPawardseachyear,uptoasteadystateofapproximately$50millioninannualfundingafter5years.IfSTRAPfundingforcertainprojectscanbeassembledbyintegratingexistingawards,thislevelofannualfundingcouldbereducedoradditionalprojectscouldbepursued.ItisanticipatedthatfundingforacompleteSTRAPwouldtypicallyrequire$5-10millionoveramultiyearperiodaveragingabout$2millionperyear.However,fundingforeachSTRAPwillbedeterminedbythespecificneedsoftheapproveddevelopmentprogram,andfundingforanyparticularSTRAPmayvaryconsiderablyfromprogramaverages.
Projectswillgenerallybefundedinannualincrementsbasedontheproposedbudget,subjecttosuccessfulachievementofagreed-uponmilestones(seebelow).UponarecognizedneedtoterminateaSTRAPduetotheinabilitytoreachthetranslationalgoalasdeterminedbythemilestonereviewgroup,investigatorswillbepermitted,dependingonthereasonformilestonefailure,tonegotiateupto75%ofthecurrentbudgetfor1moreyear.15Thiswillassistinpromotingthestabilityofestablishedtranslationalresearchteams.
Industryorfoundationco-fundingwillnotbearequirementforaSTRAPproposal.However,industryfinancialorin-kindsupportorfoundationfinancialsupportthatacceleratesachievementofSTRAPgoalswillbeviewedfavorably.Whereappropriate,NCIwillengagetheassistanceoftheFoundationforNIHinidentifyingpotentialexternalcollaboratingfundersforSTRAPawards,andwillassistSTRAPprincipalinvestigatorsinnegotiationofsuchsupport.
Solicitation and Award Process
Topicsforeachyear’sSTRAPsolicitationwillbedeterminedthroughthenewprioritizationprocess(seeCoordinatedManagementInitiativeA4).Asinglesolicitationwillbeissued,identifyingtheprioritizedconceptsfortheyear.ThesolicitationwillbepreparedbytheTranslationalResearchSupportOfficewiththeactiveinvolvementofDivisionalprogramstaffwhohavescientificexpertiserelevanttotheprioritizedconcepts.
15 TheTRWGrecognizesthatimplementationofsuchafundingstrategymaybecomplexandwillrequireNIH-levelreview.
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Awardswillbemadefromasinglepooloffunds,ratherthanreservingspecificfundingforeachprioritizedconcept.However,awardswillnotnecessarilybelimitedtooneperprioritizedconcept.Guidelineswillallowforthefundingoftwoormoreawardsforprojectspursuingalternateapproachestothesameearlytranslationalresearchgoalifthecompetingproposalsareequallymeritorious.Conversely,issuanceofthesolicitationwillnotimplyacommitmenttofundproposalsforeveryprioritizedconcept.Fundingmightnotbegrantedifproposalsresponsivetoaparticularconceptarejudgednottobecompetitivewiththoseforotherconceptsoriftherequiredbudgetsaretoolargetofundprojectsforallsolicitedconcepts.
ForSTRAPsthatinvolveacomplete,de novoprogramofactivity,acooperativeagreementmechanismislikelytobemostappropriate,althoughacontractmechanismcouldbeusedaswell.ForSTRAPsthatareconstructedviaintegrationofexistingawards,asupplementalfundingmechanismwillberequiredtofillinthemissingcomponentsofthedevelopmentalpathway,andprocedureswillbeneededtointegrateexistinggrantsintoacoordinatedendeavorsubjecttotherequiredmilestone-basedreviewandotherappropriaterequirements(seebelow).
STRAPproposalswillbereviewedbyaSpecialEmphasisPanelconvenedforreviewofproposalsinresponsetoagivensolicitation.Toensureappropriateexpertiseforevaluationoftheproposals,thepanelswillincludememberswhoareexperiencedinpreclinicaldevelopmentandmanufacturing,projectmanagement,andacademic-industrialcollaboration,inadditiontoencompassingscientificdomainsrelevanttotheprioritizedconceptstargetedbythesolicitation.Therewillalsobeanextramuralstandingoversightcommitteetoprovidecontinuityandabroaderperspectiveonoverallprogramobjectives.Oncethereviewsarecomplete,theTranslationalResearchOperationsCommitteewillrecommendasetofawardstotheExecutiveCommitteeforfunding.
Management
EachSTRAPproposalwillincludeacompleteprojectplan,addressingactivitiesthroughearly-stageclinicalorpopulationtrials.Inadditiontoaddressingtheresearchanddevelopmentactivitiestobeconductedandtheresourcesrequired,eachprojectplanmustincludeawell-developedmanagementplanaddressingthefollowing:a)governance,organizationalstructure,andprojectmanagement;b)approachestocommunicationandcoordination;c)theprocessformakingdecisionsonscientificdirection,allocationofresources,publications,andintellectualpropertyissues;andd)proceduresforresolvingconflicts.AsdescribedinOperationalEffectivenessInitiativeC1,NCIprojectmanagementresourceswillalsobeavailableforSTRAPawardsandtheprojectswillbehighlyfacilitatedbyNCIstaff.
EachSTRAPawardwillbegovernedbyaSteeringCommitteecomprisingtheseniorinvestigatorfromeachcomponentoftheawardandtheTranslationalResearchSupportOfficestaffmemberservingastheSTRAPprogramofficerandprojectmanager.16ThisSteeringCommitteewillhaveoversightresponsibilityfortheentireprojectincludingallocationofresources,participationinreviewofprogressagainstmilestones,andoverallcoordinationoftheproject.EachSTRAPprojectwillalsohaveanexternaladvisorycommittee,composedofscientific,clinical,andproductdevelopmentexpertsrelevanttothespecificproject,aswellasapatientadvocatewithprioradvisoryexperiencewithintheNCIsystem.Theadvisorycommitteewillparticipateinmilestonereviews(seebelow)andideallywillincludeatleastsomemembersofthereviewpanelthatrecommendedtheparticularSTRAPaward.
Milestones
EachSTRAPproposalwillincludeaspecificsetofdevelopmentmilestones,definedbyreferencetotherelevantTRWGdevelopmentalpathway(s),includingdatesbywhichsuchmilestonesareexpectedtobeachieved.Thereasonablenessoftheproposedmilestonesforchartingefficient,timely,yetrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.DefinitivemilestonesanddateswillbeestablishedatthetimeofawardthroughnegotiationbetweenNCIandtheprincipalinvestigators.
16 Initially,TranslationalResearchSupportOfficestaffwillserveastheofficialSTRAPprogramofficerandprojectmanager,butwithactivein-volvementofadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperiencetoguidethespecificprojectinquestion.AstheSTRAPprogramexpands,itmaybepreferabletotransfertheprogramofficer/projectmanagerresponsibilitiestorelevantDivisionalstaffatthetimeofaward.
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AsecondaryobjectiveoftheSTRAPprogramistoimprovethelikelihoodthatanyfailureofadevelopmenteffortwillbe“productive”or“informative”;i.e.,thatknowledgegainedwillbeofsubstantialvalueinfocusingfutureresearch.Inevaluatingprojectproposals,NCIwilltakeintoaccountthedegreetowhichsuchknowledgeacquisitionisbuiltintothedesignofmilestones.
EachSTRAPawardwillbesubjecttoongoinginformalmonitoringbytheSteeringCommittee,aswellasarigorousformalreviewbytheSteeringCommitteeandtheexternaladvisorycommitteeatthetimeofeachprojectedmilestone.Ongoinginformalmonitoringwillhaveseveralpurposes,includingto:
• Ensurethattheperceptionofprojectprogressonthepartofboththeprincipalinvestigator(s)andtheresponsibleNCIprojectmanagerisconsistent,accurate,andup-to-date.
• Ensurethatproblemsareidentifiedandaddressedinatimelymannerandthatnomajorproblemfirstbecomesapparentatthetimeofaformalmilestonereview.
• Anticipateforthcomingformalmilestonereviewsandfacilitatetimelygenerationofneededdocumentarysupport.
• Enableformalmilestonereviewstobemovedforwardwheneverprogresswarrants.
• Anticipateforeseeablefailurestoreachmilestonesanddevelopcontingencyplans.
FormalmilestonereviewsinvolvingtheprojectSteeringCommitteeandtheexternaladvisorycommitteewillbeusedtomakearecommendationtoNCIoncontinuation,modification,orterminationoftheproject.Whenappropriate,STRAPmilestonereviewwillbeintegratedwithreviewbytheRAID,RAPID,orDCIDEprograms(seeTailoredFundingProgramsInitiativeB5).Inaddition,wheneverprojectsreachthepointofPhaseIIclinicaltrialdesign,theSTRAPSteeringCommitteewillcoordinatemilestonereviewsanddesignactivitieswiththeongoingclinicaltrialprioritizationeffortsofanyrelevantdisease-specificScientificSteeringCommitteeestablishedasaresultoftheClinicalTrialsWorkingGroupReportimplementation.
AnnualSTRAPreportswillincludeadescriptionofprogresstowardappropriatemilestones.Ifprogresstowardamilestoneisbehindschedule,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbemodifiedorterminated.SuchrecommendationswouldbetheresultofSteeringCommitteeandexternaladvisorycommitteedeliberations.
Development/Commercialization Strategy
EachSTRAPproposalwillincludeaproposedlate-stagedevelopmentandcommercializationstrategy.Thestrategywilldescribetherequirementsandpotentialoptionsforbothlater-stagehumantestingandeventualproductcommercializationand/ordisseminationtothelargercommunity.Iftheultimategoalisacommercialproduct,whetherfortesting,therapy,orprevention,thestrategywillincludeadescriptionoftheoptimalstageforindustryhandoffandpotentialcommercializationpartners.Thestrategywillalsoincludeanintellectualpropertyplanforprotectingandlicensingpotentialinventionsandwilldescribeanylicenseormaterialtransferagreementsalreadyinplace.Thestrengthandfeasibilityofthislate-stagedevelopmentandcommercializationstrategywillbeanimportantcriterionininitialreviewofSTRAPproposals.
Investigator Credit for Participation
InvestigatorswhoparticipateinSTRAPswillbecreditednotonlyforsuccessfulhandoffofanewproductorinterventiontolate-stagetrials,butalsoforconductofSTRAPactivitiesinawaythatmaximizesthedevelopmentofscientificinsightandthetimelyrecognitionofdevelopmentfailureforprojectsthatarenotabletoachievetheintendedgoal.
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Program Evaluation
TheTranslationalResearchSupportOfficewilldevelopaplanforevaluationoftheSTRAPprogram,includingtheidentificationofbothprocessandoutcomemeasures.Continuationoftheprogramafterthefirst5yearswillbesubjecttoanevaluationoftheeffectivenessofitsimplementationandofpreliminaryevidenceconcerningtranslationalimpact.Continuationorexpansionoftheprogramafter10yearswillbesubjecttoanevaluationthataddressestheimpactandproductivityoftheprogram.AswithallNCIprograms,long-termcontinuationwillbesubjecttoexternalpeerreviewandtoweighingofprioritiesinlightofneeds,opportunities,andbudgetconditions.
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Initiative B4: Establish a funding program for early translational research that requires academic/industry collaboration involving resource sharing and/or co-funding.
Rationale
AdvancingmostNCI-fundedcancerdiscoveriesintoproductsofbroadutilityforpatientsorthecommunityrequirestheeventualparticipationofindustry.Therefore,NCIhasdevelopedseveralprogramsthatencourageindustrycollaborationinthedevelopmentofnewagents,devices,andotherinterventions.However,NCIdoesnothaveaprogramspecificallyfocusedonjointindustry/NCIfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementaryskillsandexpertiseofacademicinstitutionsandpharmaceuticalandbiotechnologycompaniestopursuespecificearly-stageproductdevelopmentopportunities.
TheAcademicPublic-PrivatePartnershipProgram(AP4),whichwasrecentlyeliminatedduetobudgetconstraints,focusedonassemblingmultidisciplinaryteamsinvolvingacademicresearchcenters,pharmaceuticalandbiotechnologycompanies,nonprofitagencies,andgovernmentorganizations.EachAP4centerwastodevelopabroadscopeofresearchprojectsratherthanpursueasingle,focusedprojecttoachieveaspecificproductdevelopmentgoal.Similarly,althoughtheNetworkforTranslationalResearch:OpticalImaging(NTROI)programrequiresindustrycollaboration,itsupportsbroadresearchprogramsratherthanatargeteddevelopmenteffort.TheDivisionofCancerTreatmentandDiagnosisfundsinvestigator-initiatedgrantsthatsupportdrugdiscovery,butthisprogramdoesnotfocusonearly-stageproductdevelopmentorhandofftoindustry.TheMolecularTargetedDrugDiscovery(MTDD)programprovidesfundingtoanacademicresearchcenterorasmallbusinessforidentificationofnewtherapies,andtheNationalCooperativeDrugDiscoveryGroups(NCDDGs)programfundsresearchfordiscoveryofnewanticancerdrugs.However,neitherprogramrequirescollaborationbetweenacademicandindustrialresearchers.Finally,althoughthegoaloftheCentersofCancerNanotechnologyExcellence(CCNE)programisthedevelopmentofnewtherapiesandindustrycollaborationisrequired,thisprogramonlyfundsnanotechnologyresearch.
Anewfundingprogramthatspecificallyrequiresacademic/industrycollaborationhasthepotentialtospeedthepaceandproductivityofearlytranslationalresearchinseveralways.First,itwillcapitalizeonthecomplementarystrengthsofindustryandacademia.Second,itwillfacilitatethetransferofacademicearlytranslationalresearchsuccessestolater-stagedevelopmentbyindustry.Third,itwillencourageindustrytopursuepromisingopportunitiesthattheywouldnotundertakeontheirown,includingprojectsfocusedonpediatricandrarecancersorminority/underservedpopulations.Finally,itwillallowNCItoleverageindustryfundingtopursueopportunitiesthathaveahigherpotentialtobetakenforwardbyindustry.
Bothindustryandacademiahavedemonstratedinterestinthetypesofcollaborativerelationshipsenvisionedbysuchanewprogram.ThisisevidencedbythesuccessparticipantsintheAP4PlanningGrantprogramexperiencedinstructuringrelationshipswithindustrialpartnersandtheestablishmentofsimilarstateprograms,suchastheUniversityofCaliforniaDiscoveryGrantprogram,whichfundscollaborativerelationshipsbetweenUniversityresearchersandCalifornia-basedcompanies.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
NCIwillestablishanewprogramdesignedtofundinvestigator-initiatedacademic/industrycollaborativeearlytranslationalresearchprojectsviaaU-seriesmechanism.TheprogramwillfundprojectsthatadvanceadiscoveryorsetofdiscoveriesalongoneoftheTRWGdevelopmentalpathwaysthroughearlyhumantestingofaspecificdrug,biologic,diagnostic/screeningtest,orothertherapeuticdiagnosticorpreventativeintervention.Theprogramwillbedesignedtoencourageprojectsthatfocusonrarecancers,pediatriccancers,orissuesinvolvingminority/underservedpopulationsthat
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arelesslikelytoattracttheinterestandinvestmentofindustrywithoutNCIinvolvement.ThisprogramisfundamentallydifferentfromtheSTRAPprogram(seeTailoredFundingProgramsInitiativeB3)inthatindustryparticipationandco-fundingarerequired,notoptional,andbecausetheprojectsareproposedbyinvestigatorsratherthanbeingdrivenbysystem-widepriorities,asisthecaseforSTRAPawards.
Theprogramwillrequireactiveparticipationandco-fundingbyatleastoneindustrypartner.TheTranslationalResearchSupportOfficewillworkwithNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirector,asappropriate,indevelopingthisinitiativeandwillalsoworkwiththeOfficeofLiaisonActivitiesandtheFoundationforNIHtoinvestigateopportunitiesforjointfundingbyfoundationsforspecificprojects.Thesizeanddurationoftheawardswillbedeterminedonaproject-specificbasis,vianegotiationbetweenNCIandtheprincipalinvestigator(s),inlightoftherequirementsofthespecificprojectplan.Thus,aprojectcouldbefundedfor6monthstopursueaveryspecificshort-termgoalorfor5ormoreyearstopursueamorecomplex,involveddevelopmentplan.
Industry Relations Working Group
Inordertolaythegroundworkfornegotiationofthejointfundingarrangementsunderlyingthesenewacademic/industrycollaborationawards,NCIwillestablishanIndustryRelationsWorkingGroupundertheauspicesoftheAdvisoryCommitteeandwithlogisticalsupportfromtheTranslationalResearchSupportOffice.Themembershipwillbecomposedof8-10individualsfromindustryandNCIrepresenting:
• Alargebiotechnology/pharmaceuticalcompany
• Asmallbiotechnology/pharmaceuticalcompany
• Devicedevelopment
• Imagingagentdevelopment
• Drugdevelopment
• Biologicsdevelopment.
TheWorkingGroupwillreviewpastexamplesofinteractionsbetweenNCIandindustry,drawingfromseveralusecases,suchasintellectualpropertylicensing,accesstoagents,andCooperativeResearchandDevelopmentAgreements.TheWorkingGroupwillbeaskedtoreportwithin1yearonthefindingsandrecommendationsderivedfromitsinvestigation,consultation,andconsensus-buildinginthefollowingareas:
• ActionsNCIcantaketoimproveNCI-industryinteractions
• NewapproachesNCIcanimplementforNCI-industryinteractions
• ActionsNCIcantaketoeliminatebarrierstoeffectiveNCI-industryinteractions.
ThefindingsoftheWorkingGroupwillbeshared,asappropriate,withNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorfordisseminationinsupportofeffortstofosterindustryrelationshipsacrossNIH.
Funding
Approximately$5millionwillbeallocatedtonewacademic/industrycollaborationseachyear,uptoasteadystateofapproximately$25millioninannualfundingafter5years.Itisanticipatedthatfundingforacompleteproject(includingbothNCIandindustrycomponents)wouldrequire$5-10millionoveramultiyearperiod,averaging$1-2millionperyear.However,fundingwillvarywiththenatureandsizeoftheproject.Forexample,smaller,morenarrowlyfocusedprojectscouldbefundedfor$500,000orless,whilelarger,morecomplexprojectscouldbefundedformorethan$10million.
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Projectfundingwillbedistributedinaccordancewiththemilestonesprovidedinthedevelopmentplan(seebelow).Uponaward,theresearchteamwillbeprovidedwiththefundingrequiredtomeetthefirstmilestone,plusadditionalfundingtosupport6monthsofworkfollowingthemilestoneduedate.Thiswillensurecontinuedfundingfortheresearchwhilethemilestonereviewiscompleted.Ifthemilestonereviewispositive,fundingwillbeprovidedforreachingthenextmilestone(plusthe6-monthextension).17
Solicitation and Award Process
NCIwillissueaRequestforApplicationswithmultipleannualsubmissiondates,solicitingproposalsforjointlyfundedacademic/industrycollaborativeprojects.ProposalswillbereviewedbyaSpecialEmphasisPanelcomposedoftranslationalexpertsdrawnapproximatelyequallyfromindustryandacademia,18withadditionalinputfromtheadvocacycommunity.Toensureappropriateexpertiseforreviewandevaluationoftheseprojects,thereviewpanelwillincludememberswithexpertiseinprojectmanagement,drugdevelopment,andintellectualpropertyinadditiontoappropriatescientificexpertiseandacademicorindustrialexperience.
Management
Eachproposalwillincludeacompleteprojectplan,coveringallactivitiesthroughtheprojectedhandoffoftheproduct,device,orinterventiontofurtherdevelopmentbytheindustrypartner.Inadditiontoaddressingtheresearchanddevelopmentactivitiestobeconductedandtheresourcesrequired,eachprojectplanmustalsoincludeawell-developedmanagementplanaddressingthefollowing:a)governance,organizationalstructure,andprojectmanagement;b)approachestocommunicationandcoordination;c)theprocessformakingdecisionsonscientificdirectionandallocationofresources;andd)proceduresforresolvingconflicts.AsdescribedinOperationalEffectivenessInitiativeC1,NCIprojectmanagementresourceswillbeavailablefortheseprojects.Aprojectmanagermaybeoneoftheresourcesthattheindustrialpartnercontributestotheproject.
EachprojectwillbegovernedbyaSteeringCommitteecomposedoftheseniorinvestigatorfromeachcomponentoftheproject(includingindustryinvestigator(s))andtheTranslationalResearchSupportOfficestaffmemberservingastheProgramOfficerandprojectmanager.19TheSteeringCommitteewillhaveoversightresponsibilityfortheentireproject,includingallocationofresources,reviewofprogressagainstmilestones,andoverallcoordinationoftheproject.Eachprojectwillalsohaveanexternaladvisorycommittee,composedofscientific,clinical,andproductdevelopmentexpertsrelevanttothespecificproject,drawnequallyfromindustryandacademia,aswellasapatientadvocatewithprioradvisoryexperiencewithintheNCIsystem.Theadvisorycommitteewillparticipateinmilestonereviews(seebelow)andideallywillincludeatleastsomemembersofthereviewpanelthatrecommendedtheaward.
Industry Participation
Participationandcost-sharingintheresearchprojectbyatleastonecompanywillberequired.Multipleindustrialpartnerswillbepermittedifthereisastrongscientificortechnicalrationale.Industrialpartnerswillgenerallybeexpectedtofund50%ofthetotaldirectprojectcostsplusapplicableindirectcosts.Someorallofthatfundingcanbein-kindprovisionofmaterials,services,orresearchwork.Aco-investigatorfromindustrywillberequired,andtheproposalwilldescribethenatureoftheinteractionbetweentheacademicinstitutionandtheindustrialpartner,thetimecommitmentoftheindustrialresearcher(s),thenatureoftheworktobeperformedbyindustry,andthecost-orresource-sharingplan.Collaborationsinvolvingmorethanoneacademicpartnerwillalsobepermittedbutnotrequired.
17 TheTRWGrecognizesthatimplementingsuchafundingstrategymaybecomplexandwillrequireNIH-levelreview.18 TheTRWGrecognizesthatitmaybechallengingtorecruitindividualsfromindustryforthesereviewpanelsduetopotentialconflictsofinterest.19 Initially,TranslationalResearchSupportOfficestaffwillserveastheofficialprogramofficerandprojectmanager,butwithactiveinvolvement
ofadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperiencetoguidethespecificprojectinquestion.Astheprogramexpands,itmaybepreferabletotransfertheprogramofficer/projectmanagerresponsibilitiestorelevantDivisionalstaffatthetimeofaward.
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Intellectual Property
Aspartoftheproposaldevelopmentprocess,theindustrialandacademiccollaboratorswillnegotiateanintellectualpropertyagreement,includingpublicationandpatentrights,thatwillbeincludedwiththeproposal.Adraftagreementwillberequiredatthetimeofproposalsubmission,withthesignedagreementrequiredatthetimeofaward.
Aspartoftheintellectualpropertyagreement,theindustrialpartner(s)willhavea“rightoffirstrefusal”foranyintellectualpropertydevelopedundertheproject.However,iftheindustrialpartnerdeclinestofurtherdevelopthetechnologyorproduct,theacademicinvestigatorsandNCIwillhavetherighttopursuefurtherdevelopmentandnegotiatelicenseswithotherindustrialpartners.Theintellectualpropertyagreementwilladdresscompensationtotheoriginalindustrypartnerifaproductissuccessfullycommercializedbysuchafollow-onpartner.
Milestones
EachproposalmustincludeadetailedtimelineanddevelopmentplanwithappropriatemilestonesdefinedbyreferencetotherelevantTRWGdevelopmentalpathway.Thereasonablenessoftheproposedmilestonesforchartingefficient,timely,andrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.DefinitivemilestonesanddateswillbeestablishedatthetimeofawardthroughnegotiationbetweenNCIandtheprincipalinvestigator(s).
EachprojectwillbesubjecttoongoinginformalmonitoringbytheSteeringCommittee,aswellasarigorousformalreviewbytheSteeringCommitteeandtheexternaladvisorycommitteeatthetimeofeachprojectedmilestone.Ongoinginformalmonitoringwill:
• Ensurethattheperceptionofprojectprogressonthepartofboththeprincipalinvestigator(s)andtheresponsibleNCIprojectmanagerisconsistent,accurate,anduptodate.
• Ensurethatproblemsareidentifiedandaddressedinatimelymannerandthatnomajorproblemfirstbecomesapparentatthetimeofaformalmilestonereview.
• Anticipateforthcomingformalmilestonereviewsandfacilitatetimelygenerationofneededdocumentarysupport.
• Enableformalmilestonereviewstobemovedforwardwheneverprogresswarrants.
• Anticipateexpectedfailurestoreachmilestonesanddevelopcontingencyplans.
Annualreportswilladdressprogresstowardappropriatemilestones.Ifprogresstowardamilestoneisbehindschedule,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbemodifiedorterminated.SuchrecommendationswouldbetheresultofSteeringCommitteeandexternaladvisorycommitteedeliberations.
Milestone Review
FormalmilestonereviewsinvolvingtheprojectSteeringCommitteeandtheexternaladvisorycommitteewillbeusedtomakeafinalrecommendationtoNCIoncontinuation,modification,orterminationoftheproject.Ifamilestoneisachievedaheadofschedule,thereviewwilloccurwhenthemilestoneisachievedandfundingcanbeaccelerated.
UpondeterminationoftheSteeringCommitteeandtheexternaladvisorycommitteethatamilestonehasbeenmetsuccessfully,thenextroundoffunding,sufficienttocompletethenextmilestoneplus6monthsofwork,willbereleasedtotheresearchteam.Thisfundingprocesswillcontinueuntileitheramilestonehasnotbeenmetortheprojectiscompleted.IftheSteeringCommitteeandtheexternaladvisorycommitteedeterminethatthemilestonehasnotbeenmet,noadditionalfundingwillbereleasedandtheawardwillbeterminated.Theongoinginformalmonitoringprocessshouldanticipatethissituationandallowtheinvestigatorstoplanforterminationoftheproject.
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Program Evaluation
TheTranslationalResearchSupportOfficewilldevelopaplanforevaluationoftheacademic/industrycollaborationfundingprogram,includingtheidentificationofbothprocessandoutcomemeasures.Continuationoftheprogramafterthefirst5yearswillbesubjecttoanevaluationoftheeffectivenessofitsimplementationandpreliminaryevidenceconcerningtranslationalimpact.Continuationorexpansionoftheprogramafter10yearswillbesubjecttoanevaluationthataddressestheimpactandproductivityoftheprogram.AswithallNCIprograms,long-termcontinuationwillbesubjecttoexternalpeerreviewandweighingofprioritiesinlightofneeds,opportunities,andbudgetconditions.
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Initiative B5: Integrate access to GMP/GLP manufacturing and other preclinical development services more effectively with milestone-driven early translational research projects.
Rationale
Availabilityofpreclinicaldevelopmentservices,especiallymanufacturingofclinical-gradematerials,isperceivedtobeamongthebiggestbottlenecksinbringingdiscoveriesfromthelaboratorytotheclinic.DespitethesuccessofNCI-fundedmanufacturingandpreclinicaldevelopmentresourceprogramssuchasRAID,RAPID,andDCIDE,accesstothesedevelopmentcapabilitiesisstillarate-limitingstepfortranslationalresearchingeneral.IntegratingaccesstotheseserviceswiththenewtailoredtranslationalresearchfundingprogramsproposedbytheTRWGwillenhancetheproductivityofNCIinvestmentsintranslationalresearchandthedevelopmentservicesrequiredtobringproductstotheclinic.Itwillalsoensurethatdevelopmentresourcesarereadilyavailableforhigh-priority,milestone-drivenearlytranslationalresearchprojects.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
Currently,thereviewoftranslationalresearchprojectsisnotcoordinatedwiththereviewsconductedbyNCI-supportedpreclinicaldevelopmentresourceprograms.Anapplicationfordevelopmentresourcesrequiresaseparateinvestigator-initiatedapplicationandreviewprocessthatisindependentofthereviewandapprovalofprojectscoveringearlierstepsinthetranslationalpathway.Thislackofintegrationisperceivedbyinvestigatorstocauseasignificantadditionaldelayforprojectsthathavereachedthestagewheredevelopmentservicesareneeded.
UnderthemodifiedP50/U-seriesguidelinesandthenewSTRAPfundingprogramforprioritizedprojects(seeTailoredFundingProgramsInitiativesB1andB3),allmajortranslationalresearchprojectswillbesubjecttoobjective,formal,milestone-basedreview.Fortheseprojects,accesstothedevelopmentcapabilitiesrepresentedbyRAID,RAPID,andDCIDEwillnotoccurviathestandardapplicationandreviewprocesses,althoughtheseprocesseswillcontinuetoberequiredforinvestigator-initiatedprojectsnotsubjecttomilestone-basedreview.Rather,thereviewprocessesestablishedbyRAID,RAPID,andDCIDEwillbeintegratedwiththenewtranslationalresearchmilestone-basedreviewprocesses.Suchanintegratedreviewwillensurethatwhenaprojecthasachievedalloftherequiredmilestonesandisreadyfortoxicology/pharmacologytestingandclinicalgrademanufacturing,itwillneedtoundergoonlyonecoordinatedreviewtomoveforward.Thisintegratedreviewisnotintendedtoaffectorcompetewiththereviewandfundingoftraditional,investigator-initiatedRAID,RAPID,andDCIDEapplications.
Integrated Review
Theintegratedreviewprocesswillbeimplementedasfollows.Whenasuccessfultranslationalresearchprojectisnearingthestagewherepreclinicaldevelopmentresourcesareneeded,therelevantprogramofficerwillcontactstafffromeitherRAID,RAPID,orDCIDE,asappropriate,toorganizeacoordinatedreview.Thiscoordinatedreviewwillinvolvetheindividualsandcommitteesinvolvedinthestandarddevelopmentresourcesreviewprocessaswellastheexternaladvisorycommittees,steeringcommittees,principalinvestigators,projectmanagers,programstaff,etc.,thatwereinvolvedwithpreviousmilestonereviewsforthetranslationalresearchprojectinquestion.
Forexample,RAIDnowusesatwo-tieredreviewprocess—anoversightcommitteeandaninitialreviewcommitteethatisasubcommitteeoftheoversightcommittee.Theinitialreviewcommitteeiscomposedofmembersoftheoversightcommitteeplus,ifnecessary,additionalexpertsinthescienceandproductiontechnologyrelevanttotheapplicationinquestion.TheoversightcommitteeiscomposedofindividualsfromNCI,academia,andindustrywhohaveexperience
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indevelopingnewanticanceragents.20Theoversightcommitteerecommendsfundingbasedonreviewoftheapplicationsgivenasufficientlyhighpriorityscorebytheinitialreviewcommittee.Theserecommendationsarebasedonscientificmerit,feasibility,practicaldevelopmentconsiderations,andNCIpriorities.Theoversightcommitteealsoconductsperiodicreviewsoffundedprojectstoevaluateachievementofmilestonesandadherencetotimelinesaswellastodecideoncontinuation.
Formilestone-basedtranslationalresearchprojectsrelevanttoRAID,aRAIDinitialreviewcommitteewillbeinvolvedinthecoordinatedreview,andtheRAIDoversightcommitteewillprioritizetherecommendedprojectsforfunding.Thus,thenewNCAB-approvedRAIDreviewprocesswillconstitutetheintegrated“back-end”ofthenewmilestone-based“front-end”reviewprocessforthesetranslationalresearchprojects.
Theintegratedreviewprocesswillevaluatethefollowingcriteria:
• Scientificquality
• Importanceofclinicalneed
• FitwithNCI-widetranslationalresearchpriorities
• Strengthandfeasibilityofthepreclinicaldevelopmentplan,includingappropriatenessofmilestones
• Strengthandfeasibilityoftheenvisionedclinicaldevelopmentplan
• Projectedcostofthedevelopmentprogram
• Experienceoftheprincipalinvestigatorandtheinstitutionindrugdevelopment,includingInvestigationalNewDrugApplication(IND)submissions
• Strengthofintellectualpropertyprotectionandresolutionofanyintellectualpropertyissues.
Project Management
Asatranslationalresearchprojectproceedsthroughpreclinicaldevelopment,itwillbeoverseenbytheprogramandprojectmanagementstaffinvolvedinearlierstagesoftheproject(seeOperationalEffectivenessInitiativeC1)andbyprojectmanagementand/orprogramstafffromtherelevantdevelopmentresourcesprogram.Theprojectwillbereviewedatpredeterminedmilestonesbythesameintegratedprocessdescribedabove,withfundingforeachstagecontingentonsuccessfulcompletionofthemilestone.
Funding
Becausethecostofmanufacturingandotherpreclinicaldevelopmentservicesissubstantial,fundsfortheseserviceswillnotbeincludedinspecifictranslationalresearchawards.Rather,eachyear,theTranslationalResearchOperationsCommitteewillrecommendreservingaportionofthededicatedtranslationalresearchbudgetinaset-asidepoolofcontractfundsforpreclinicaldevelopment.ThesefundswillbeallocatedbytheExecutiveCommitteebasedonrecommendationsfromtheOperationsCommitteeconcerningwhichprojects,approvedthroughtheintegratedreviewprocessdescribedabove,arethehighestpriorityforuseofthesepreclinicalcontractdevelopmentfunds.Theserecommendationswillbebasedonavailablefunds,fitwithNCI-widetranslationalresearchpriorities,estimatedcostsofcompletingdevelopment,andcompetingneedsandopportunitiesacrossdiseasesites,TRWGpathways,patientpopulations,etc.Asmanyprojectswillrequiremorethan1yeartocompleteallpreclinicalwork,someportionoftheset-asideeachyearlikelywillberequiredtofulfillongoingcommitments.ThiscontractfundingwillbeinadditiontocurrentRAID,RAPID,andDCIDEfundingforindependentinvestigator-initiatedprojects.TRWGmembersbelievethisisacriticallyunderresourcedareaoftranslationalservices.Thenewportfoliocodingandcoordinatedtranslational
20 ReportoftheWorkshoptoReviewtheNationalCancerInstitute’sRapidAccesstoInterventionDevelopment(RAID)Program,November2005.Availableat:http://dtp.nci.nih.gov/docs/RAID/RAIDFinalReport061406.pdf.
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researchmanagementsystemisenvisionedtomakethismoreapparentandprovidethesystem-widecredibilitynecessarytowarrantincreasedinvestment.
Involvement of Development Experts in Translational Research Review
DevelopmentexpertsinvolvedintheRAID,RAPID,andDCIDEreviewprocesseswillbeincorporated,asappropriate,inearlierstagesofreviewingmilestone-basedtranslationalresearchprojectsfundedthroughthemodifiedP50andU-seriesprogramsandthenewSTRAPfundingprogram.Involvementofdrug,biologics,orimagingagentdevelopmentexpertsearlierintheprocesswillhelpensurethatprojectsarenotadvancedthathaveahighprobabilityofencounteringseriousroadblocksintoxicology,pharmacology,ormanufacturing.Moreover,theseexpertscansharelessonslearnedandbestpracticeswithinvestigatorsattheinitialphasesofaprojecttobetterinformtheapproachtaken.ThistypeofearlyinvolvementandcollaborationwillensurethatRAID,RAPID,andDCIDEprogramstaffandexternalreviewersbecomemoreintegratedwiththeoveralltranslationalresearcheffort.
Molecular Analysis Assay/Device Preclinical Development Resource Program
TheTranslationalResearchSupportOfficewillworkwiththeDivisionofCancerTreatmentandDiagnosisandtheDivisionofCancerPreventiontoevaluatetheneedforandpotentialbenefitsofanNCIdevelopmentresourcesprogramtodevelopandvalidatebiomarkermolecularanalysisassaysanddevicesforuseinNCI-supportedprojects.Theevaluationwillalsoaddressthetechnicalandfinancialrequirementsofsuchaprogramandthepotentialthatindustrymightlicensecertainofthedevelopeddevices.
Use of Industry Excess Capacity
ItmaybepossibletotakeadvantageofexcesscapacityatpharmaceuticalandbiotechnologycompaniesiftheservicesarenotavailablethroughNCIdevelopmentprograms.TheTranslationalResearchSupportOfficewillinvestigatewhethersuchexcesscapacityexists,forwhatservicesitexists,andtheinterestofindustryinmakingtheseservicesavailableatareasonablecosttoNCI-fundedacademicresearchers.
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Operational Effectiveness
Introduction
InadditiontoimprovingmanagementcoordinationacrossNCIandstrengtheningfundingprograms,theTRWGidentifiedanumberofspecificopportunitiestoenhancetheoveralloperationaleffectivenessoftranslationalresearch.
Onekeyimprovementwouldbetheavailabilityofcriticalprojectmanagementresourcestoassistlarge,multiproject,collaborativetranslationalresearchprogramsinachievingtheirgoals.Industryhaslongusedformalprojectmanagementapproachestofacilitatetheirdevelopmentprogramsbyensuringcommunicationacrossprojectteams,efficientlyidentifyingresources,coordinatingtransitionsbetweendevelopmentalstages,andsolvingproblems.ManyofthemorecomplexNCI-supportedtranslationalresearchprogramswouldbenefitfromsuchfacilitation.
Asecondcriticalareaforimprovementisincoreservices.Enhancedcoordinationacrossinstitutionsandprogramsisneededtoensurethatresourcesarenotinvestedinduplicativeinfrastructuresandthatservicesoperateinacost-effectivemanner.Inparticular,increasingdemandforhigh-quality,annotatedbiospecimensrequiresenhancedstandardization,dedicatedfunding,andapproachesforefficientandequitablesharingofavailablespecimens.
CollaborationsamongNCI,academicinstitutions,industry,andfoundationsarefundamentaltothesuccessoftranslationalresearch.Suchcollaborationsshouldbepromotedbystreamlininglegalnegotiationsandbuildingpartnershipsthatleveragecomplementaryskillsandresources.Finally,theneedforacontinuingflowofqualifiedtranslationalresearcherschallengesthecurrentsystem,whichisdesignedprimarilytotraineitherlaboratoryscientistsorclinicians.Acriticalevaluationoftrainingprogramsandcareerincentivesisneededtochartacleareducationandcareerdevelopmentpathfortranslationalresearchprofessionalsandothersengagedinmultidisciplinarytranslationalresearchteams.
ToachievethisdiversesetofobjectivesforimprovingtheoperationaleffectivenessofNCI-supportedtranslationalresearch,theTRWGproposessixinitiatives.
C1. Establish a formal project management system for early translational research.
C2. Establish a system to coordinate core services essential for early translational research.
C3. Enhance quality and accessibility of annotated biospecimen repositories and associated analytic methods.
C4. Develop enhanced approaches for negotiation of intellectual property agreements and agent access.
C5. Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research.
C6. Enhance training and career incentives for early translational research.
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Initiative C1: Establish a formal project management system for early translational research.
Rationale
Themultidisciplinarynatureoftranslationalresearchandtheneedtointegratesequentialstepsalongcomplexdevelopmentalpathwayswarrantstheprovisionofdedicatedprojectmanagementresources.CreationofaformalprojectmanagementsystematNCI,incorporatingspecificmanagementcompetenciesandclarifyingresponsibilityforkeyfunctionalroles,wouldspeedthetranslationalresearchprocessbyaddressingseveralimportantmanagementtasksthatarenotconsistentlyrealizedundercurrent,informalarrangements.
Thesetasksinclude:
• Identifyingandaccessingspecializedresourcesandexpertisesuchasmanufacturingcapabilitiesandregulatorysupport
• Coordinatingandcommunicatingbetweentheprojectscientificleadsandthemultidisciplinaryprojectteamtoensurethatprojectplanmodificationsareimplementedsmoothlyandthatproblemsareidentifiedandaddressedinatimelyfashion
• Coordinatingthetransitionofprojectsacrossdevelopmentstages,disciplines,andprograms
• Ensuringefficientprogressandadheringtoamilestone-basedprojectplan.
Projectmanagementhaslongbeenusedbyvariousindustries,includingpharmaceuticalandbiotechnologycompanies,toefficientlymoveresearchanddevelopmentprojectstowardtangibleproducts.Inaddition,severalacademicinstitutionshaveestablishedprojectmanagementpositionstoassistwiththeirlocaltranslationalresearchprograms.ImplementationofanNCIprojectmanagementsystemwouldbringthesebenefitsconsistentlytoallmajorNCI-fundedtranslationalresearchprograms.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Scope of Projects Covered
Projectmanagementresourceswillbeprovidedforthefollowingcategoriesoftranslationalresearchprojects:
• Multiprojectcollaborativetranslationalresearchawards(i.e.,P50,U-series,andRFA-directedP01awards)21
• ProjectsfundedviathenewSTRAPprogram(seeTailoredFundingProgramsInitiativeB3)
• Researchprojectsfundedviathenewprogramthatrequiresacademic/industrycollaboration(seeTailoredFundingProgramsInitiativeB4)
• PhaseIandIIclinicaltrialcontracts.
TheprojectmanagementsystemwillbeimplementedbyincludingprojectmanagementintheguidelinesforP50,U-series,andP01awardsaswellasPhaseIandPhaseIIclinicaltrialcontractsandthenewSTRAPandacademic/industrycollaborationprograms.Theseprojectsmayalsorequestandallocatefundstosupporttheservicesofaninstitutionallybasedprojectmanager.
21 NotethattheprojectmanagementsystemwillonlyberequiredforP50andRFA-directedP01awardsifguidelinescanbemodifiedtorequiretheuseofNCIprojectmanagementresources.Ifmodifyingtheguidelinestoincludethisrequirementisnotpossible,investigatorsfortheseawardswillbestronglyencouragedtoutilizeNCIprojectmanagementresourcesfortheirprojects.
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Overall Approach
TheTranslationalResearchSupportOfficewillberesponsibleforensuringthattheprojectmanagementfunctionsdescribedbelowareprovidedforalldesignatedprojects.ForP50,P01,andU-seriesawardsandPhaseIandIIclinicaltrialcontracts,theproposedprojectmanagementfunctionswillbeperformedprimarilybycurrentprogramstaffinconjunctionwithanewprojectmanagementpositionwithineachappropriateDivision,Center,orOffice.Theseprojectmanagerswillserveasaresourceforprogramstaffrequiringguidanceorassistanceinfulfillingprojectmanagementfunctions.TheprojectmanagerswillalsoworkcloselywiththeTranslationalResearchSupportOfficeprojectmanagementstaffinimplementingandcoordinatingprojectmanagementfunctions.
ProjectmanagementwillbeimplementedinitiallyforP50,U-series,andRFA-directedP01awardsandPhaseIandIIclinicaltrialcontractsasthoseguidelineswillberevisedbeforetheinitialSTRAPandacademic/industrycollaborationawardsaremade.ForthenewSTRAPandacademic/industrycollaborationawards,SupportOfficestaffwillserveasbothprogramofficersandprojectmanagers.TheSupportOfficewillalsoprovidecertainprojectmanagementfunctions(e.g.,overviewandinventoryofresources)forallapplicableprojects.Mostimportantly,SupportOfficestaffwillserveasthecoordinatingfocusofresponsibilityforensuringthatthedistributedprojectmanagementsystemdescribedabovefunctionseffectively.ThiswillincludecoordinatingtheactivitiesofprojectmanagementstaffintheDivisions,Centers,andOffices;communicatingwiththeextramuralcommunityconcerningthevalueprovidedbytheNCIprojectmanagementsystem;andcommunicatingwithNCIleadershipconcerningprogressandanyissuesthatmayarise.
Following2yearsofimplementation,theprojectmanagementsystemwillbeevaluated.Oneaspectoftheevaluationwillbetodetermineifthedistributedmodel,withmostprojectmanagementfunctionsvestedintheDivisions,Centers,andOffices,hasbeeneffective,orwhetheramorecentralizedmodelshouldbeconsidered.Iftheconclusionisthatprojectmanagementhasprovidedsignificantvalue,adecisionwillbemadewhethertoexpandtheavailabilityofNCIprojectmanagementresourcestoincludeinvestigator-initiatedR01sandP01sthatprimarilyinvolvetranslationalresearchasidentifiedbythenewlyestablishedtranslationalresearchawardcodes(seeCoordinatedManagementInitiativeA3).
Project Management Staffing
Translational Research Support Office. TheTranslationalResearchSupportOfficeprofessionalstaffwillincludeindividualswithskillsandexperiencerelevanttoprojectmanagement(e.g.,industryinteraction,regulatorycompliance,interactionwithacademicinstitutions).AtleastoneSupportOfficeseniorprofessionalwillhaveadoctoraldegreeinarelevantscientificfield,orequivalentexperience,aswellasdirectprojectmanagementexperience,preferablywithinanindustryenvironment.Additionalstaffwithprojectmanagementexpertisewillbeaddedasprojectdemandsgrow.Cross-trainingwillbeprovidedsothatotherSupportOfficestaffmembershaveskillsincertainaspectsofprojectmanagement.
Divisions/Centers/Offices. AtleastoneprojectmanagementpositionwillbeestablishedwithineachDivision,Center,andOfficetoassistprogramstaffinprovidingprojectmanagementservices.Theseprojectmanagerswillhavedirectprojectmanagementexperience,preferablywithinanindustryenvironment,andwillworkcloselywithTranslationalResearchSupportOfficestafftoensuredevelopmentandoperationofacoordinated,well-functioningprojectmanagementsystem.Todrivesuccessfulimplementationofprojectmanagementresponsibilitiesbyprogramstaff,suchresponsibilities,includingcoordinationwiththeTranslationalResearchSupportOffice,willbeincludedintheirperformanceplans.
Project Management Roles and Responsibilities
System-Wide Roles and Responsibilities. TranslationalResearchSupportOfficestaffwillberesponsibleforcoordinatingtheformalprojectmanagementsystemanddirectlyprovidingthefollowingprojectmanagementfunctionsforallapplicabletranslationalresearchprojects.
1.Cross-NCICoordinationandCommunication.TheSupportOfficewillmaintainanoverviewandinventoryoftranslationalresearchprojectsacrossallNCIorganizationalunitsandprogramsandfacilitatecoordinationbetweenprogramswhereincreasedsynergyand/ordecreasedredundancycouldberealized.Inaddition,theSupportOffice
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willarrangeregularforumswithprojectmanagementandprogramstafffromtherelevantDivisions,Centers,andOfficestodiscussprogrammaticprojectmanagementneeds.SupportOfficestaffwillalsointeractwithextramuralinvestigatorsandinstitutionallybasedprojectmanagerstodiscussprojectmanagementneeds.
2.ResourceInventoryandDatabase.TheSupportOfficewillmaintainaninventoryanddatabaseofthefollowingresources,oftenneededbytranslationalresearchprojects,whicharecurrentlyavailableacrossNCI,academicinstitutions,andindustry:
High-throughputscreening
Biospecimenrepositories
Researchtools(e.g.,celllines,animalmodels)
Biomarkerassaysystems
Imagingcapabilities
Agents,devices,orothermaterials/informationfromindustry
Developmentcapabilities,includingmanufacturing,toxicology,andpharmacology
Biostatisticalanalysisservices
Patientpopulations.
SupportOfficestaffwillcoordinateassemblyoftheinventoryandworkwiththeNCICenterforBioinformatics(NCICB)todesignandbuildthedatabase.ThisdatabasewillbeanexpansionoftheNCI-supportedcoreservicesdatabasedevelopedaspartofOperationalEffectivenessInitiativeC2.Programstaffandprojectmanagerswillusethisinventorytodirectinvestigatorstoneededresources.Thisinventoryalsowillbeavailabletoinvestigatorspreparingproposalsinresponsetotranslationalresearchsolicitationstoassistthemwithdevelopingfullyresponsiveproposals.
3. OversightRole.SupportOfficestaffwillbeavailableforconsultationwithprincipalinvestigatorswhohaveconcernsregardingprojectmanagementfunctionsprovidedbyprogramstaff.
Project-Specific Roles and Responsibilities. Programstaffwillberesponsibleforprovidingproject-specificprojectmanagementfunctionsfortheapplicableP50,P01,andU-seriesawardsandPhaseIandIIclinicaltrialcontractsinconsultationwiththeirunitprojectmanagementstaff.FortheSTRAPandacademic/industrycollaborationawards,thesefunctionswillbeprovidedbyTranslationalResearchSupportOfficestaff,whowillserveasprogramofficersandprojectmanagersforthoseawards.
1. ResourceIdentification.Programofficerswillworkproactivelywithprincipalinvestigatorstoidentifyresourcesneededateachstageofatranslationalresearchproject.ThisincludesfacilitatingcontactsandcollaborationsthroughwhichprincipalinvestigatorscanobtainaccesstoresourcessuchasthoselistedintheTranslationalResearchSupportOfficedatabase.
2. RegulatoryFilings.Programofficerswillassistwithregulatoryfilings,asnecessary,workingwithprincipalinvestigatorsandotherNCIprogramstaff.AnyInvestigationalNewDrug(IND)applicationswillbepreparedincooperationwiththeRegulatoryAffairsLiaisonfromtheCancerTherapyEvaluationProgramandotherrelevantintramuralorextramuralparties.
3. CoordinationandCommunication.Programofficerswillassistprincipalinvestigatorsinensuringconsistentandmeaningfulcommunicationamongallmembersofamultidisciplinary,multiprojecttranslationalresearchteam.Thiswillincludeorganizingregularmeetingsfordiscussionandplanning,identifyingpointsofcommunicationbreakdown,andcoordinatingthetransferofprojecttasksbetweengroupsthatmaybefromdifferentinstitutions.
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4. MonitoringProgressandProblemSolving.Programofficerswillworkwithprincipalinvestigatorstomonitorcontinuedprogressoftranslationalresearchprojectsaccordingtoestablishedprojectmilestones(seethesectionsonmilestoneswithintheTailoredFundingProgramsInitiativesB1,B3,andB4)andtoassistwithsolvinganyproblemsthatarise.Theywillorganizeappropriatemilestone-basedreviewsandprovideinputtothesteeringorexternaladvisorycommitteesthatarechargedwithdecidingwhetheraprojectshouldbecontinued,modified,orterminated.
5.CollaborationwithInstitutionallyBasedProjectManagers.Programofficerswillcollaboratewithinstitutionallybasedprojectmanagers(seebelow),asneeded,tofacilitatetheresearchprogram.Thismayincludecoordinationconcerningwhichprojectmanagementfunctionswillbefulfilledbyeachprojectmanagerandassistinginsolvingday-to-daymanagementissuesfortheproject.
Institutionally Based Project Managers
AlthoughtheNCIprojectmanagementsystemwillprovidevaluableassistanceformajorlong-termmanagementissues,large,complexprojectsoftenencounterday-to-dayissuesthatrequiremorelocalprojectmanagementsupport.TranslationalResearchSupportOfficestaffandprogramofficerswillfocusonbroader,globalissuesrelatedtoaproject,whileinstitutionallybasedprojectmanagerswillfocusonnarrower,localissues.
TheguidelinesforSTRAPandacademic/industrycollaborationawardswillrequireaninstitutionallybasedprojectmanagementplanandallowawardeestorequestfundingforprojectmanagementsupport.TheguidelinesformultiprojectcollaborativeP50,P01,andU-seriestranslationalresearchawardsaswellasPhaseIandIIclinicaltrialcontractswillbemodifiedtoencourageonsiteprojectmanagementandallowforfundingofinstitutionallybasedprojectmanagers.
Itisnotanticipatedthateachtranslationalresearchprojectorawardwillhaveadedicatedinternalprojectmanager.Rather,individualinstitutionallybasedprojectmanagersmightprovidesupportforseveraldifferentprojects,witheachawardcontributingfundstosupporttheposition.Oneoptionwouldbeforcancercenterstoestablishaprojectmanagementcoreresourcethatwouldserveandbeadditionallysupportedthroughcharge-backsfromthecenters’variousSTRAP,academic/industrycollaboration,P50,P01,andU-seriestranslationalawardsaswellasPhaseIandIIclinicaltrialcontracts.
Theexactrolesandresponsibilitiesofaninstitutionallybasedprojectmanagerwillbedeterminedbytheprincipalinvestigatorandspecifiedinthefundingapplication.However,thefollowingprovidesageneraloverviewofthetypesoffunctionsthatinstitutionallybasedprojectmanagersmaybeassigned:
• Prioritizeteamactivitiesandmakerecommendationsonappropriatecoursesofactioninresponsetoprojectresults.
• CoordinatewiththeprincipalinvestigatorandNCIstaffontheallocationofresourcesinthemosteffectivefashion,givencurrentprioritiesandtimelines.
• Facilitateaccesstoinstitutionaland/orregionalcoreservicestomeetprojectneeds.
• Developimplementationplans,timelines,andbudgets.
• Ensuretimelycontributionsbyallteammembers.
• Conductregularteammeetingsandensurethatactionitemsareexecuted.
• Identifypotentialbottlenecksandworkwithallteammembers,theprincipalinvestigator,andNCIstafftoresolveimpediments.
• Preparenon-INDregulatoryfilings.
• Prepareprogressreportsasneeded.
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Project Management Training
Formaltraininginprojectmanagementiscrucialtoensurethatprojectmanagershavetherequisiteskills.Therefore,SupportOfficestaffandanyNCIprogramofficerswithprojectmanagementresponsibilitieswillbeprovidedwithformaltraining.Projectmanagementtrainingforinstitutionallybasedprojectmanagerswillbeanallowablecostfortheaward.
Severalprojectmanagementtrainingprogramsexist,includingwithinbusinessschools,professionalassociations,andprivateorganizations.TheTranslationalResearchSupportOfficewillconductananalysisofcurrentlyavailableprojectmanagementtrainingprogramstodetermineiftheywillprovidetheskillsandtrainingneededformanagementofacademictranslationalresearchprojects.Ifexistingprogramsaredeterminedtobeinadequate,SupportOfficestaffwillworkwithproviderstotailorprogramstomeetNCItranslationalresearchneeds.
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Initiative C2: Establish a system to coordinate core services essential for early translational research.
Rationale
NCIhaslongrecognizedthevalueofconsolidatedcentersthatprovidecriticalinfrastructuresupport,includingcoreservices,asdemonstratedbytheestablishmentofcancercentersbeginningin1961.TheClinicalandTranslationalScienceAwards(CTSA)programrecentlyestablishedaspartoftheNIHRoadmaphassimilarobjectives.ThenewCTSAprogram,togetherwiththedevelopmentoverthepastseveralyearsofseveralotherNCIprogramsthatsupportcoreservices,providethepotentialofcreatingindependent,perhapsredundant,coreservicesinfrastructures.Thishasledtoconcernamongthecancerresearchcommunitythatcoreservicessupportingtranslationalresearchneedtobemoreeffectivelycoordinated,withcapacitywellmatchedtoneed.
Developingamoreefficientandcoordinatedcoreservicesnetworkwillfacilitateandaccelerateaccesstoabroadrangeofservicesandensurethatservicesareavailableinacoordinatedandcooperativemanneracrossfundingprograms.Itmayalsominimizeredundancies,ensureefficiencyandeconomyofscalebyoperatingservicesatoptimalcapacity,andincreasestandardization,qualityassurance,andcross-corereliability.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Analysis of Existing Core Services
TheTranslationalResearchSupportOffice,withassistancefromotherNCIandcontractorstaffasnecessary,willanalyzeNCI-fundedintramuralandextramuralcoreserviceswiththegoalofidentifyingpossiblefunctionalredundancies.Thisanalysiswillrequireaninvestigationoffundedcoreawards(i.e.,facilities,equipment,infrastructure,stafftime,supplies)todistinguishbetweentotallyindependentcoresforthesameserviceatasingleinstitutionversuscoresthatutilizethesamecorefacilityandequipmentandsimplyprovideincrementalfundingforstafftime,supplies,specificservices,etc.
Identification of Existing Core Services. DuringtheTRWGportfolioanalysis,apreliminarylistof1,364coreawardswasgeneratedthatincludesCancerCenters(P30s),SpecializedProgramsofResearchExcellence,andP01sbyinstitution.Asnodatabasecurrentlyexiststhatmaintainstheinformationforallextramuralcores,thislistwasassembledfromdataprovideddirectlybytheCancerCentersprogram,theidentificationofcoresontheComputerRetrievalofInformationonScientificProjects(CRISP)database,andbysearchingtheSPOREWebsiteorindividualabstractsontheCRISPdatabase.AllP30coresareincludedonthislist,butthecoreslistedforSPOREandP01awardshavenotbeenverifiedandmightnotbecomplete.Inaddition,coresfundedthroughU-seriesprograms,R24awards,etc.,arenotincluded.ThispreliminarylistofP30,P50,andP01coreserviceawardsincludes93U.S.institutionswiththemajority(55%)fundedthroughCancerCentergrants,followedbySPORE(27%)andP01(18%)grants.
Inordertodevelopacomprehensivelistofalltranslationalresearchcoreservices,thisinitiallistwillbeexpandedtoincludeallSPOREandP01cores,coreslocatedattheintramuralCenterforCancerResearch,andanycoresassociatedwithU-seriesawards,CTSAawards,etc.GrantapplicationsandprogressreportsforallSPOREandtranslational22P01awardsnotincludedinthecurrentlistandalltranslationalU-seriesawardswillbeanalyzedtoidentifyfundedcoresanddeterminewhetherthecorefundssupportself-containedservicesorareusedtoprocureservicesfromanalreadyexistingcorefacility.ThisinformationwillbeusedtoassembleacomprehensivelistofallNCI-fundedtranslationalresearchcoreservices.
Analysis for Redundancies. Thecomprehensivelistoffundedcoreswillbereviewedtoidentifypotentialredundanciesatindividualinstitutions.BasedonthelistofcorespreparedaspartoftheTRWGportfolioanalysis,itappearsthat“redundanciesbytitle”(i.e.,morethanonecoreofasingletypeataninstitution)existprimarilyforbiostatistics/bioinformatics,clinicaltrials,andtissuecores.However,because“redundancybytitle”doesnotnecessarilyequateto
22 P01awardscategorizedastranslationalforthisanalysiswillbethoseidentifiedintheoriginalTRWGportfolioanalysis.
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actualredundancy,afunctionalassessmentisrequiredtodeterminethenatureoftheoverlap.Forexample,althoughbiospecimencoresmayhavecertainaspectsthatareuniquetotheorgansiteorstudy,otheraspectssuchasadministration,ITsupport,equipment,etc.,mightbeappropriatelyconsolidated.
Thefunctionalassessmentwillinvolveanalyzinggrantapplicationsandthemostrecentprogressreportsforthosecoresataninstitutionthatappeartoberedundantaccordingtotitle.Basedontheexistinglistof1,364cores,thereare733(54%)thatareredundantbytitle.Thegoaloftheanalysisistodetermineifthesecoresarefunctionallyredundantorwhethertheyutilizeacommoncoreinfrastructure.Ifpossible,thisanalysiswillalsoincludecoreservicesfundedinwholeorinpartbythehostinstitution.
Consolidation of Core Services
Iftheredundancyanalysisidentifiesinstitutionswherethereistrueduplicationofoneormoresignificantcoreserviceinfrastructures,aplanforconsolidationwillbedeveloped,includingananalysisofanyfinancialimpactfromtheproposedconsolidation.Forinstitutionswithcancercenters,consolidationwillbeachievedbystrengtheningtheroleofcancercentersastheprimaryprovidersofcoreservices.Forinstitutionswithoutcancercenters,individualawardeeswillbeexpectedprimarilytouseexistinginstitutionalservicesorthoseofneighboringinstitutions.Consolidationwillbepromotedbyadjustingreviewcriteriatorewardcollaborationandresourcesharingincoreservices.Asgrantscomeupforrenewal,consolidationwillbeimplementedaccordingtotheplandevelopedforthatinstitution.
GuidelinesforCancerCenterandP50,U-series,andRFA-directedP01awardswillberevisedasnecessarytoincorporatethefollowingprinciplesforcoreservicesresourcesharing.
1. Cancercenterswillprovidethecoreservicesinfrastructureforkeytranslationalresearchresourcesatinstitutionswithcancercenters.
2. IndividualP50,U-series,P01,andotherrelevantawardswillrequestfundseithertoaccesscancercenterorotherinstitutionalcoreservicesorformaterials/salarysupportforprojectstafftousethoseservices.
3. NewtranslationalresearchRequestsforApplicationsandProgramAnnouncementswillspecifyuseofcancercenterorotherinstitutionalcoreservices.
4. Ifapplicantsconsiderrequiredcoreservicesnonexistentorunavailableattheircancercenterorinstitution,theymustpresentalistoftherelevantcoreservicesthatdoexistandaspecificrationaleforcreationoftheproposednewcores.
5. Ifaserviceisnotavailableataninvestigator’shomeinstitution,apreferredoptionwillbetoprovidefundstousetheservicesofaneighboringinstitution.
6. Noawardwillmandatethecreationofaseparatecoreserviceifanappropriatecoreserviceislocallyavailableatcancercenters,thehomeinstitution,ortheNCIintramuralprogram.
Guidelineswillbechangedtoformallyrewardsharingofcoreservicesandfacilities.WhilecancercenterandSPOREguidelinesalreadyspecifythatcoreresourcesandfacilitiesshouldbeshared,additionalincentivesinthereviewprocessareneededtoencourageefficiency.Cancercenterguidelineswillbemodifiedtoprovideformalrecognitionduringthegrantrenewalprocessforcorefacilitiesthatprovideservicestoinvestigatorsorprojectsfundedbyotherprogramsorinstitutions.
Comprehensive, Publicly Accessible Core Services Database
AdatabasewillbecreatedcontainingregularlyupdatedinformationonallNCI-fundedcoreservices.ThedatabasewillinitiallyfocusonkeyNCI-fundedtranslationalresearchcoreservices,butcouldbeexpandedtoincludecoreservicesfundedbyCTSAs,otherNIHInstitutes,academicinstitutions,andindustry.Twocomponentsofthedatabasewillbenecessary:1)arestrictedportionthatwillbeusedbyNCIreviewersandprogramofficers,and2)apublicportionthat
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willbeopentotheresearchcommunity.SuchadatabasewillserveasausefultoolforNCIprogramstaffwhentheyaredeterminingwhetherornottofundanewcoreserviceataninstitution.
DatabasedevelopmentwillbetheresponsibilityoftheNCICenterforBioinformatics,workingincoordinationwithTranslationalResearchSupportOfficestaff,NCIprogramstaff,andextramuralinvestigatorsandwillbeimplementedinaccordancewiththecaBIG™designprinciplesandstandards.Thisdatabasewillserveasafoundationfortheexpandedresourcedatabasedevelopedinsupportoftheprojectmanagementsystem(seeOperationalEffectivenessInitiativeC1).
Potential Data Fields. NCICBandTranslationalResearchSupportOfficestaffwillworkwithNCIprogramofficersandrepresentativesfromboththeintramuralandextramuralresearchcommunitiestodefinetheimportantdatafieldstocollect.Potentialfieldsinclude:
• Typeofservice
• Specificcapabilities
• Availableequipment
• Numberofusers
• Numberofprojectssupported
• Numberofstudies,analyses,etc.,performed
• Numberofsamplesprocessed
• Percentofcapacitycurrentlyinuse
• Coreservicecosts
• Averageturnaroundtime
• Otherfundingsourcesforthefacility.
Thedatabaseisultimatelyintendedtoraisestandardsandencouragebestpractices.Therefore,incorporationofauserratingfeature(e.g.,aratingscaleandcommentssection)willbeconsidered.
Reporting System and Data Submission. ReportingandupdatinginformationinthedatabasewillbecomearoutineobligationofallNCIawardsthatsupportanindependentcoreservicesfacility,regardlessoffundingprogram.Datawillbecollectedandmanagedonacore-by-corebasisandthedatabasewillretainacumulativerecordofactivity.Atinstitutionswherecancercentersexist,informationonallcoreserviceswillbeheldandmaintainedcentrallyandreportedbythecancercenter.
Design Principles. Coreserviceprincipalinvestigatorswillsubmitastandardizedelectronicfilecontainingspecificdataontheircoreservicesthatwillserveasthebuildingblocksforanonlinedatabase.ThisonlinedatabasewillthenbeavailabletoNCIstaffandinvestigatorsthroughaunified,Web-basedinterfaceorportalthatshieldstheuserfromthemechanicsoftheunderlyingsystem.Thesystemwillbedesignedsuchthatinvestigatorscanupdatetheircoreservicesdataonanas-neededbasis.Controlledaccesswillbegrantedthroughappropriatespecializedinterfacestoallotherusersforauthorizedpurposes.
Database Functionality. Thedatabasewillprovidethefollowingstandardfunctions.
1. Searches.Thedatabasewillbeequippedwithsoftwaretoolsthatallowsearchesonanyfieldorcombinationoffields,usingkeywordsorcombinationsofkeywords.Searchingwillbefacilitatedwithpredefinedmenusofkeywordoptions(e.g.,typeofservice,geographiclocationofparticipatingcenters).
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2. Reporting.Bothinteractiveandbatch-modereportingwillbesupported,andpredefinedreporttemplateswillbeavailableforcommonsearchrequests.
3. AccessControls.Accessprivilegeswillbedefinedtoaddressthediverseneedsofdatabaseusers.Twousercategoriesareenvisioned:
• Extramuralinvestigatorsfrombothacademiaandindustrywillhaveaccesstofundamentalinformationsuchaslocationofcores,servicesoffered,capacity,costofservice,contactinformation,etc.
• NCIprogramstaffwillhaveaccesstoalldatainthesystem,includingrawdatathatmightbeusefulforreview(e.g.,numberofusersofthecore,otherfundingfortheservice),aswelldataaccessibletoextramuralinvestigators
Regional Centers of Excellence
Overall Approach. Ascoreservicesarestreamlinedandconsolidated,regionalcenterswillbeestablishedforhighlytechnical,service-based,equipment-orexpertise-intensivecoreservicesthatcannotbeasefficientlyoperatediflocatedateverycancercenterorotherresearchinstitution.Theresearchworldisalreadyevolvingtowardstheconceptofregionalornationalcentersofexcellence.TheHumanGenomeSequencingCentersareanexampleofnationalcores,whichareselectedbyanadvisorycommittee.
TheAdvisoryCommitteewillconveneaWorkingGroupofNCIprogramstaffandextramuralinvestigatorstoidentifyalistofcoreservicesthatarecandidatesforregionalization.Coreservicesthatwouldpotentiallybenefitfromcreationofregionalcentersornetworksinclude:
• GMP/GLPmanufacturing
• Massspectrometry
• State-of-the-artproteomics
• High-throughputgenomics/SNPanalysis
• Imagearchivingand/oranalysis.
Identifying and Selecting Regional Centers. Oncethecoreservicesappropriateforregionalizationhavebeenidentified,NCIwilldetermineifappropriateregionalcentersalreadyexistfortheidentifiedservicesorwhetherneworexpandedcentersarerequired.Ifneworexpandedcentersarerequired,NCIwillissueanRFAsolicitingproposalsforestablishmentofsuchcenters.TheRFAwillstipulatethescopeandqualityofservicetobeprovided,theprojectedusage,etc.Successfulapplicantswillreceivefundingforthecoreinfrastructureandabaselinelevelofserviceactivity.Thecoreswillbedesignedtoexpandinresponsetoincrementalfundingfromusers.Regionalcenterslikelywillbebasedatcancercenters,thoughthisshouldnotbealimitingrequirementintheRFA.
Thetransitiontoregionalcentersneednotbeadrasticchangefromthestatusquoandshouldnotrequirethecreationofnewfacilities.Rather,oncecentersareestablished,grantsrequiringtheservicewillbefundedforusingtheservice.Ingeneral,individualinstitutionswillnotbefundedforprovidingacoreserviceavailablefromaregionalcenter.
Oversight and Management. Regionalcoreservicecentersmusthaveamanagementplantoensureadequateaccessbyinvestigatorsfromotherinstitutionsandappropriatestandardizationandqualitycontrol.Inordertoensurequality,efficiency,andaccessibility,TranslationalResearchSupportOfficestaffwillbeinvolvedwithoversightoftheregionalcenters.
Standardization and Quality Assurance. Regionalcoreservicecenterswillestablishstandardizedprocesses,qualitycontrol,etc.,toensurecomparabilityofdataandhigh-qualityoutputs.TranslationalResearchSupportOfficestaffwillworkwithextramuralresearcherstodeterminewhichservicesneedtobestandardizedorcertifiedtoensurecomparability
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betweeninstitutions.OversightandcertificationprocesseswillbeestablishedbytheSupportOfficeincoordinationwiththeregionalcenterprincipalinvestigatorstoensurethatcoreservicesandfacilitiesmaintainstate-of-the-artequipment,procedures,etc.
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Initiative C3: Enhance quality and accessibility of annotated biospecimen repositories and associated analytic methods.
Rationale
Continuingadvancesingenomicandproteomictechnologiesaredrivinganincreaseddemandbythetranslationalresearchcommunityforstandardized,high-quality,clinicallyannotatedhumanbiospecimens.However,biospecimenresourcesofsufficientqualitytomeetthetechnicalrequirementsofthesenewanalytictoolsfallfarshortofthedemand.Thisshortageofannotatedbiospecimens—collected,processed,transported,stored,andanalyzedusingstandardoperatingprocedures—isakeybarriertotranslationalresearch.Threeothertranslationalresearchbarriersassociatedwithbiospecimenshavealsobeenidentified.Thefirstbarrieristheabsenceofstandardizedanalyticmethodsthatcanobtainconsistent,standardizeddatafrombiospecimensregardlessofthecollectiontechnique.Thesecondbarrieristhelow-levelrepresentationincurrentrepositoriesofspecimensfromminoritypopulations.Thethirdbarrieristhelow-levelrepresentationofprecancerousspecimenswhichareessentialforeffectivetranslationalresearchfocusedonprevention.Anenhancedsystemofbiospecimenrepositoriesandanalyticmethodswouldimprovestandardization,qualityassurance,andreliability,whileminimizingaccessbarriersandstrengtheningthecomprehensivenatureofthiskeytranslationalresearchresource.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Enhancingthequalityandaccessibilityofannotatedbiospecimensforuseintranslationalresearchwillrequireatwo-prongedapproach.Thefirstistoexpandthenumberoffullyannotatedbiospecimenscollected,processed,transported,andstoredusingstandardizedoperatingprocedures.However,sincesuchprocedureswillonlybeappropriateforuseinmajoracademicmedicalcenters,thiswilllimitthetotalnumberofspecimensavailableforresearch.Therefore,aparallelapproachwillbetoincreasetheoverallnumberofbiospecimens,especiallythosefromminoritypopulations,byencouragingsmallercentersandnonacademichospitals—especiallythosethatarepartoftheNewCommunityCancerCentersProgram(NCCCP)—tocollectandfullyannotatebiospecimensundercarefullycontrolled,butnotuniformlystandardized,procedures.Thesespecimenscanthenbeusedforstudiesexaminingresearchquestionsthatdonotnecessitateahighdegreeofstandardizationandwithstandardizedanalytictoolsthatgiveconsistentresultswithtissuesobtainedundervariableconditions.
Reinforce Ongoing Standardization Efforts
TheNCIOfficeofBiorepositoriesandBiospecimenResearch(OBBR)wasestablishedin2005toaddressthekeybarriersinbiospecimencollection,standardization,andstorage.OBBRiscurrentlyworkingtodevelopandimplementstandardsthatwillenableanationalcancerbiospecimenresourceinfrastructureandpromotespecimenanddatasharingtofacilitatemulti-institutional,high-throughputgenomicandproteomicstudies.Tothisend,OBBRhasproposedFirstGenerationBiorepositoryGuidelines(FGGs)toharmonizepoliciesandproceduresforNCI-supportedbiospecimenresources,includingclinicalandepidemiologicalannotationandpatientprivacyaspects.23TheTRWGstronglyendorsestheseOBBRactivitiesandproposesthefollowingadditionalapproachestofurtherenhancetheirmission.
Modification of Guidelines
Guidelinesforcancercenters,SPOREs,cooperativegroups,andotherlargeNCI-specificprogramsthatinvolvebiospecimencollectionwillberevisedasnecessarytoincorporateuseoftheFGGsastheyarefinalized.Prospectively,recipientsoftheseawardswillberequiredtoadheretostandardizedcollection,storage,retrieval,anddisseminationprocedurestopromoteconsistencyandcomparabilityofderiveddatabetweeninstitutions.Standardizationwillnotpertainsolelytotumortissue,butalsotonormalandpremalignanttissues,aswellasancillaryspecimens.Reviewcriteriafor
23 FirstGenerationGuidelinesforNCI-SupportedBiorepositories,April2006.Availableat:http://biospecimens.cancer.gov/biorepositories/guide-lines_full_formatted.asp.
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cancercenters,SPOREs,andotherNCI-specificprogramswillbemodifiedtoformallyrewardstandardizedcollectionofbiospecimens.
Suchmodificationswilldictateaculturalshiftfromaninvestigator-centrictoacollaborativeapproachtobiospecimens.Cooperationandbuy-inwillberequiredfromInstitutionalReviewBoards(IRBs)andinformaticsgroups.SelectedNCIprograms(e.g.,theCancerGenomeAtlasBiospecimenCoreResource,theClinicalProteomicTechnologyAssessmentforCancerInitiative,theNCCCP)havealreadyincorporatedtheFGGsintorecentRFAsandRFPsandcanbeusedasmodelsforguidelinerevision.
Funding for Biospecimen Collection
Untiltherealexpenseofstandardizedbiospecimencollectionandstorageisfundedasaseparatecost,suchstandardizedcollectionwillneverbecomewidespread.Inthepast,pathologydepartmentscollectedtissueswithoutbeingpaidtodoso,butmanyinstitutionswillnolongerallowthispractice.Furthermore,evenwhenaninstitutionisreimbursedforspecimencollection,thefundsarenotalwaysallocatedtothepathologistsresponsibleforthetissues,resultinginanunwillingnesstocooperate.
Fundingforbiospecimencollectionrelatedtoclinicaltrialsshouldbeprovidedupfrontasaportionofthetrialcostwhentissueprocurementisaspecificcomponentoftheprotocol.Guidelineswillbemodifiedtoformallyrecognizetheimportanceoffundingstandardizedspecimencollectionandstorage.Thisfundingwillbeseparablefromthelumpsumofthegrantsothatthepathologygroupreceivesthesupportdirectly.Onepossibilityistoconsidera“tethered”fundingmodelthatgivescredittomultipleprincipalinvestigatorsandallowsfundstobedividedasneeded.FundingwillbecontingentonbiospecimencollectionandstoragebeingconductedinaccordancewiththeFGGs.
Informed Consent
Inordertofacilitatecollectionofawidevarietyofsamples,enablecontinuedcollectionofdataforsampleannotation(e.g.,epidemiologicandoutcomesdata)beyondthedateofthesamplecollection,andauthorizebiospecimentestingnotanticipatedattimeofcollection,astandard,nationalinformedconsenttemplateisneeded.ThetemplatemustbecompliantwiththeHealthInformationPortabilityandAccountabilityActandtheOfficeofHumanResearchProtectionsregulations.Additionally,becauseIRBstendtomodifymostconsentformstoaccommodatelocalissues,itwillbeadvantageoustodevelopacommontemplatethatcanbepluggedintotheconsentformsusedbyanyinstitution.
Severalinformedconsenttemplatesforthefutureuseoftissueshavebeendevelopedandarecurrentlyusedincooperativegroupsandcancercenters.AnewinformedconsenttemplatehasalsobeenproposedundertheFGGs.TheBiorepositoryCoordinatingCommittee(BCC)iscurrentlyworkingtoharmonizetheseformstoestablishastandardizedtemplate.Guidelinesforcancercenters,SPOREs,cooperativegroups,etc.,willberevisedtorequireuseofthestandardizedtemplate,oncedeveloped.TheTranslationalResearchSupportOfficestaffwillassistOBBRandtheBCCwiththeseefforts.Obtainingwidespreadacceptancemayrequireorganizingexpertworkshopsincludingbioethicists,patientadvocates,patients,governmentrepresentatives,academicandnonacademichealthprofessionals,industryrepresentatives,andotherleadersinthecancerresearchcommunity.
National Biospecimen Repository Network
Therehavebeeneffortsinthepasttodevelopanintegratednetworkofbiospecimenrepositoriesservedbyacommoninformaticsinfrastructureandacommonaccessportal.Forexample,OBBRdevelopedandpilotedaNationalBiospecimenNetworkBlueprint(NBN)concept24whichoutlinesanapproachforcreatingapublic-privatepartnershiptoestablishanationalresourceofstandardized,privacy-protected,high-qualitybiospecimensforgenomic-andproteomic-basedresearch.UseofthestandardizedproceduresrequiredfortheNBNconceptwaspilotedinaseriesofProstateCancerSPOREs.However,thepilotproveddifficulttoimplementduetothechallengesofmulti-institutionalstandardizationandbiospecimensharing.TheNBNconceptmaynowbepursuedinthecontextoftheNCCCP.
24 http://biospecimens.cancer.gov/nbn/blueprint.asp.
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AdditionaleffortstoimplementtheNBNconceptarewarranted.TheTranslationalResearchSupportOfficewillworkwithOBBRtodevelopnewapproachesforimplementingsuchanationalvirtualnetworkpotentiallyincludingspecimenscollectedunderbothstandardizedandinstitution-specificproceduresandwithanincreasedfocusontheinclusionofspecimensfromminoritypopulationsandspecimensfromprecanceroustissues.Thegoalisforthenetworktolinknumerousrepositoriescontainingproperlyannotatedbiospecimens,includinglifestyleandepidemiologicinformationwherepossible.Ifsuchanetworkisrealized,programguidelineswillbemodifiedtorequirethatbiospecimenscollectedinconjunctionwithNCI-fundedclinicaltrialsbeproperlyannotatedandmadeavailableaspartofthenetwork.
Comprehensive Database. Adatabaseofallrelevantrepositorieswillbecriticaltothesuccessofabiospecimennetwork.PreviousanalysesoftheNCIbiospecimenresourceportfolioindicatedthatNCIsupportshundredsofbiospecimen-relatedactivities.BuildingontheexistingSpecimenResourceLocator,25OBBRisalreadyexploringthepossibilityofcreatingaWeb-basedcataloguetoprovidetheextramuralcommunitywithinformationonexistingbiospecimencollections.Thiscataloguecouldbeastartingpointforthedatabase.
Specimen Access. Oncethedatabaseiscreated,individualsseekingaccesstothespecimenswillsubmitanapplicationthatclearlyexplainsthenumberofspecimensneeded,theamountrequired,andthepurposeofthestudy.Applicationswillbereviewedandaccessgrantedbasedonmerit.OBBRwillberesponsiblefordevelopingandmanagingatransparent,fair,andscientificallybasedprocessforprioritizingaccesstothebiospecimens.
Industry Collaboration. Becauseanationalbiospecimenrepositorynetworkwillbeexpensivetobuildandmaintain,agovernment-industryconsortiummodelwillbeexplored.TheTranslationalResearchSupportOfficeandOBBRwillexplorewiththeFoundationforNIHthepotentialofestablishingaconsortiumofindustrypartnerswhowouldsupportthenetworkthroughcharitabledonations.TheSupportOfficewilldrawontheresourcesofNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorinsupportofestablishingsuchaconsortium.
Theindustrypartnersintheconsortiumwouldhavetheabilitytoapplyforaccesstothespecimens.Theywouldnotreceiveprioritizedaccess,butwouldhavethesameabilityasanyacademicresearchertoapplyandcompetebasedonimportanceoftheresearchprojectproposed.Companiesthatarenotmembersoftheconsortiumcouldalsoapplyforaccesstothespecimens,butwouldbechargedmoreforthosespecimensthanwouldconsortiummembers.
Inordertosuccessfullydevelopsuchaconsortium,aconvincingcasemustbepresentedtopotentialpartnersestablishingtheadvantagestheywouldreceivefromparticipation.Tosupportsuchacase,allspecimenswillneedtohaveaminimumannotationdatasetthatisattractivetoindustryandafairprioritizationprocessmustbedevelopedtoregulateaccesstothelimitedtissueresources.
Therearesomepublic/privatepartnershipsalreadyinexistencethatmightserveasmodelsforsuchaconsortium.Forexample,theInternationalGenomicsConsortium(IGC)hasaprojectcalledtheExpressionProjectforOncology(expO)thataimstobuildonthetechnologiesandoutcomesoftheHumanGenomeProjecttoaccelerateimprovedclinicalmanagementofcancerpatients.Thisconsortiumfacilitatespartnershipsbetweenacademicinstitutionsandpharmaceuticalcompaniesandhasledtothedevelopmentofastandardizedmethodoftumortissuecollectionthatisbeingusedforexpressionprofiling.26
Standardized Analytic Methods
Whilethestandardizationofbiospecimencollectionandprocessingisoneapproachtoobtaininghigh-qualitygenomicandproteomicdatafromhumanbiospecimens,itdoesnotaddressallfacetsoftheproblem.Forexample,newstandardprocedureswillnotaffecttissuesthatwerecollectedinthepastandsomeaspectsoftissuecollectionarelikelytoremainbeyondthereachofstandardization(e.g.,temperatureattimeofcollection,timeperiodoftissuedevascularization).Furthermore,improvedcollectionandprocessingtechniqueswillcontinuetobedeveloped.Therefore,specimenscollectedovertimemaynotnecessarilybeuniform.
25 http://pluto3.nci.nih.gov/tissue/default.htm.26 InternationalGenomicsConsortium:http://www.intgen.org/expo.cfm.
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Moreover,becauseuniformcollectionoftissuesunderstandardconditionsisextremelyexpensive,suchmethodswillprobablybeimplementedonlyforspecificstudiesortissues.Manyinstitutions,particularlynonacademichospitals—whichareanextremelyimportantpotentialsourceoftissue—areunlikelytoimplementthesemethodsasstandardoperatingprocedures.Therefore,inadditiontostandardcollectionandprocessingmethods,standardanalyticmethodsmustbedevelopedforusewithtissuesobtainedunderroutine,andthusvariable,conditions.
Developmentofstandardanalytictechniquesisanemergingareathatwarrantsadditionalattentionandfunding.Sucheffortsarefocusedonthedevelopmentofmethodologiesthatcanyieldconsistent,comparable,quantitative,andreproducibleanalyticresultsnomatterhoworwhenthetissuewascollected.TheNCIInnovativeMolecularAnalysisTechnologiesprogramintheOfficeofTechnologyandIndustrialRelations(OTIR),aswellasotherNCIprograms,isbeginningtosupporttheseefforts.TheTranslationalResearchSupportOfficewillworkwithOTIR,OBBR,theBCC,andrelevantprogramstafftodeterminehowthesecurrenteffortscanbeenhancedandincorporatedintofutureendeavors.
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Initiative C4: Develop enhanced approaches for negotiation of intellectual property agreements and agent access.
Rationale
Translationalresearchrequireseffectivecollaborationamongindustry,academia,NCI,andfoundations.Developingapproaches,procedures,andtoolsthatpromoterapidnegotiationofintellectualpropertyagreementsandfacilitateresearchersgainingaccesstoimportantagentswillimprovethetranslationalresearchprocessbyminimizingbarriersthatoftendelayorpreventpotentiallyproductivecollaborations.
ThreegeneralsituationscanbeidentifiedwithinNCI-fundedtranslationalresearchwhereintellectualpropertyissuesarefrequentlyproblematic:
• Industryprovidingmaterialstoacademicinstitutionsforresearchpurposes
• Exchangeofmaterialsbetweenacademicinstitutions
• LicensingofNCI-fundedintellectualpropertybyacademicinstitutionstoindustry.
Theapproachesdescribedbelowaretargetedatpromotingrapidnegotiationofintellectualpropertyagreementsinthesesituations.
Inaddition,havingavailableNCI-supportedagentrepositorieswouldreducesearchandnegotiationcostsforresearchersneedingspecificagentsfortheirresearch.Throughtheserepositories,researcherswouldbeabletoreadilyaccessagentsusingaprenegotiatedmaterialstransferagreement.Ifresearchresultswerepromising,theinvestigatorcouldthennegotiatefurtherwiththepatentowneroftheagent.Suchrepositoriescouldalsoserveasacentralizedsourceforcompoundsthatdonothavepatentprotection.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Model Agreements and Best Practices
Someofthedifficultiesinresolvingintellectualpropertyissuesresultfrombeginningnegotiationswithoutanyclearguidelines.Theavailabilityofmodelagreementsandbestpracticesshouldfacilitatenegotiations,therebyspeedingtheprocessofsharingintellectualproperty.
TheTranslationalResearchSupportOfficewillworkwiththeNCITechnologyTransferBranch(TTB)tocoordinatedevelopmentofmodelagreementsandbestpractices.Thefirststepwillbetoconductananalysisofexistingagreementsandpractices.Theanalysiswillincludebutnotnecessarilybelimitedtothefollowing:
• StandardizedlanguageforclinicaltrialandmaterialtransferagreementsdevelopedbytheCancerTherapyEvaluationProgram
• ModelagreementsandlicensingbestpracticesdevelopedbytheNIHNationalHumanGenomeResearchInstitute
• Modelagreementsdevelopedbyfoundationsandadvocacygroups
• ModellicensinglanguagedevelopedbytheAssociationofUniversityTechnologyManagers
• IntellectualpropertyagreementsdevelopedbytheplanninggrantparticipantsoftheAcademicPublic-PrivatePartnershipProgram
• MasterMaterialTransferAgreementsdevelopedbyNCIanduniversities.
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Basedontheanalysisofexistingmodels,theSupportOffice,inconsultationwithTTBandrelevantNCIprogramstaff,willdevelopmodelagreementsandbestpracticesforuseinthefollowingsituations:
• NCI-fundedacademicresearchersobtainingmaterialsfromindustry
• NCI-fundedacademicresearchersobtainingmaterialsand/orlicensingintellectualpropertyfromanotheracademicresearcher
• IndustrylicensingintellectualpropertyfromNCI-fundedacademicresearchers.
Dependingontheresultsoftheanalysis,onemodelandsetofbestpracticesapplicabletoeachsituationmaybedeveloped.Alternatively,severalmodelsandsetsofbestpracticesmaybedevelopedforeachsituation.Examplesofconditionsthatmayrequirespeciallytailoredagreementsandbestpracticesincludethefollowing:
• Early-stagedevelopmentversuslater-stagedevelopment
• Combinationstudiesversussingle-agentstudies
• Significantpotentialapplicationsversusunknownpotentialapplications
• Co-exclusivityversusasingle,exclusivelicense.
NCIwillconveneaseriesofmeetingswithkeystakeholders,includingindustrysponsors,foundationandadvocacygrouprepresentatives,andacademictechnologytransferrepresentatives,toreviewtheassembledsetofmodelagreementsandbestpractices.Thegoalofthisseriesofmeetingswillbetodevelop,withinputfromawideaudienceofstakeholders,asetofharmonizedagreementsandpractices.Activeparticipationbyindustry,academia,foundationsandadvocacygroups,andNCItoaddresstheirindividualneedswillenhancethelikelihoodthatthefinalsetofmodelagreementsandbestpracticeswillbewidelyadoptedbyboththeprivate-andpublic-sectorresearchcommunities.ThesemeetingswillbecoordinatedwithsimilarmeetingsconcerningclinicaltrialcontractsorganizedaspartoftheClinicalTrialsWorkingGroupReportimplementation.
ThemodelagreementsandbestpracticeswillbemadeavailableonapublicWebsitemaintainedbyTTBforanyresearchertoaccessanduse.UseoftheseagreementsandbestpracticesbytranslationalresearchersfundedbyNCIwillbepromotedbyarticlesincancercenterpublicationsandreferencetothepublicWebsiteinNCIgrantandprogramannouncements.Followingdevelopmentofthemodelagreementsandbestpractices,NCI,incollaborationwithindustryanduniversitytechnologytransferrepresentatives,willconductanannualreviewtodeterminewhetherchangesareneededandwhetheradditionalmodelagreementsandbestpracticesshouldbeestablished.
Alternative Approaches
Moreefficientnegotiationofindividualagreementsisnottheonlyapproachthathasbeendevelopedforaddressingintellectualpropertyissues.Otherapproachesthathavebeendevelopedandappliedinvariousfieldsincludepatentpoolsandindustry-governmentconsortia.
Patent Pools. PatentpoolshavebeenusedinseveralfieldswithintheUnitedStatesduringthelast150years,includingsewingmachinemanufacturing,aircraftmanufacturing,radioandtelevisiontransmissions,anddigitalaudiovisualtechnology.27Apatentpooliscomposedoftwoormorepatentownerswhoagreetolicensetheirpatentstoothermembersofthepatentpooloranoutsideparty.Thelicensingcanbeconductedbyeitherthemembersofthepatentpoolorbyaspecificmechanism,suchasajointventure,developedtooverseethepatentpool.Whenthepatentpoolisadministeredbyajointventure,potentiallicenseesonlyhavetonegotiatewithoneentityforpatentswithinthepoolratherthanwithseveraldifferentpatentowners,therebyreducingnegotiationcostsandtime.
27 ThishistoryanddescriptionofpatentpoolsistakenfromClarkJ,PiccoloJ,StantonB,TysonK.Patentpools:asolutiontotheproblemofaccessinbiotechnologypatents?UnitedStatesPatentandTrademarkOffice,2000.Availableat:http://www.uspto.gov/web/offices/pac/dapp/opla/pat-entpool.pdf.
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Althoughusedinseveralfields,patentpoolshavenotbeendevelopedforthebiotechnologyorpharmaceuticalindustries.AwhitepaperproducedbytheU.S.PatentandTrademarkOfficearguedforthefollowingbenefitsforbiotechnologypatentpools:28
• Eliminationofdifficultiesduetoblockingpatentsorstackinglicensesaslicenseeswillobtainaccesstoallpatentswithinthepatentpool
• Reductionoflegalcostsasdisputescanbesettledthroughthepatentpool
• Poolingoftherisksofresearchanddevelopment
• Facilitationofexchangeofinformationthatisnotprotectedbypatents.
Suchapatentpoolcouldpotentiallybepursuedforagentsdevelopedbyindustrythattheindustryhasnoplanstoexploit.Accesstotheseagentsbyacademicresearcherscouldbegovernedbyacommonsetofintellectualpropertytermsnegotiatedthroughthepool.
Government-Industry Consortia. Themostfamousexampleofagovernment-industryconsortiumisSEMATECH(SEmiconductorMAnufacturingTECHnology).SEMATECHwasformedin1987by14U.S.-basedsemiconductormanufacturersandtheU.S.Governmentwiththegoalofsolvingwidespreadmanufacturingproblemsthroughcommonlysupportedresearchanddevelopment.29Federalfundingforthisconsortiumendedin1996,buttheindustrialpartnershavemaintainedtheconsortium.Subsequently,internationalmembersandanacademicpartnerhavebeenincluded.SEMATECHholdsintellectualpropertyrightstotechnologydevelopedundertheconsortium.MembercompaniesareallowedtousetechnologiesdevelopedwithinSEMATECHwithoutanyadditionallicensing,and,afteraspecifiedtimeperiod,thetechnologiesaremadeavailabletononmembersthroughlicensingagreements.30Suchaconsortiummightbeappropriatefordevelopingalarge,comprehensive,annotatedcancerbiospecimenrepository(seeOperationalEffectivenessInitiativeC3),acomprehensiveagentrepository(seebelow),and/orcomprehensivemolecularanalysistechnologiesforcancerbiospecimens.
InconjunctionwithTTB,theTranslationalResearchSupportOfficewillevaluatethesealternativemodelstodeterminewhethertheycanbeadaptedtoNCI-fundedtranslationalresearchprojects.Ifeitheroftheseapproachesseemsfeasible,SupportOfficestaffwillbegindiscussionswithpotentialindustrypartners,inconjunctionwithTTB,todetermineinterestinformingsuchrelationships.
NCI Agent Repositories
Becauseofthepotentialbenefitsassociatedwithdecreasedsearchandnegotiationcosts,theTranslationalResearchSupportOfficewillevaluatethefeasibilityofdevelopingorenhancingthesize,quality,andaccessibilityofthefollowingtypesofagentrepositories.
Compounds without Patent Protection. Thisrepositorywouldincludecompoundsthathavelostorcannotreceivepatentprotection.Asurveyofcompoundsthathavelostpatentprotectionaswellasasurveyofnaturalproductsorotheragentsthatcannotbepatentedwillbeconductedandtheiravailabilityforinclusionintherepositoryassessed.
NCI-Developed Compounds. Thisrepositorywouldincludecompoundsdevelopedand/orcharacterizedbyNCIresearchers.AsurveyofNCIintramuralresearcherswillbeconductedtodevelopalistofcompoundsappropriateforsuchaninventory.Therequirementsnecessarytoprotecttheresearchinterestsoftheintramuralresearcherswillalsobeevaluated.
28 ClarkJ,PiccoloJ,StantonB,TysonK.Patentpools:asolutiontotheproblemofaccessinbiotechnologypatents?UnitedStatesPatentandTrademarkOffice,2000.Availableat:http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf.
29 See“SEMATECHHistory”athttp://www.sematech.org/corporate/history.htm.30 U.S.CongressionalBudgetOffice,198�.TheBenefitsandRisksofFederalFundingforSematech.Availableat:http://www.cbo.gov/showdoc.
cfm?index=6205&sequence=0.
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Compounds from NCI-Funded Extramural Researchers. ThisrepositorywouldincludecompoundsresultingfromresearchconductedunderNCIawards.AsurveyofNCItranslationalresearchgranteeswillbeconductedtoidentifycompoundsappropriateforthisrepositoryanddetermineunderwhattermssuchcompoundsmightbemadeavailabletootherresearchers.
Industrial Compounds. Thisrepositorywouldincludecompoundsprovidedbypharmaceuticalandbiotechnologycompanies.Asurveyofpharmaceuticalandbiotechnologycompanieswillbeconductedtodeterminetheirinterestinparticipatinginthisrepository.Ifinterestissufficient,aninventoryofcompoundsthatindustryiswillingtocontributewillbeassembled.
Ifdevelopingorimprovingsuchrepositoriesisfeasible,theSupportOfficewilldeveloppoliciesandprocedurestoensurethatappropriateannotatedinformationisavailableoneachsampleinanelectronic,searchableformatandthattherepositoriesaremaintainedandupdatedonaregularperiodicbasis.TheSupportOfficewillalsoworkwithNCIstaffandmanagementtoidentifyfacilitiesandfundingfortherepositoriesandworkwiththeTTBtodevelopstandardlanguagecoveringintellectualpropertyissues.
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Initiative C5: Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research.
Rationale
PartnershipsthatbringtogetherfoundationsandadvocacygroupswithNCIandacademicmedicalcentersarebecomingincreasinglyimportantinbiomedicalresearch.Suchpartnershipshaveallowedfoundationsandadvocacygroupstocontributevaluableenthusiasm,patient-centeredexpertise,and,attimes,fundingformanytranslationalresearchinitiativesandtrainingprograms.Forexample,withencouragementfromtheNIHDirector’sPanelReportin1997,severalfoundations,suchastheDorisDukeCharitableTrust,theBurroughsWellcomeFoundation,andtheHowardHughesMedicalInstitute,providedprojectfundingforclinicalresearchersanddevelopedtranslationalresearchtrainingprogramsatacademicmedicalcenters.31ItisvitaltothetranslationalresearchenterprisethatNCIfosterandstrengthentheserelationships.
Theenhancedinteractionsandcollaborationsproposedbelowaredesignedtocapitalizeonthecomplementaryskillsandresourcesoffoundationsandadvocacygroupstoadvanceearlytranslationalresearch.Theyalsoprovideanopportunitytobenefitfromthestrengthsoffoundationsandadvocacygroupsinfacilitatingintegrationofacademia,industry,NCI,andphilanthropicorganizations.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Overall Approach
TostrengthentherelationshipofNCIwithfoundationsandadvocacygroupsintheareaoftranslationalresearch,NCIshouldestablishaleadershippositionresponsiblefordevelopingandsustainingsuchrelationshipsandaddressingpotentialcollaborativeeffortsintranslationalresearchamongfoundations,includingtheFoundationforNIH,advocacygroups,andallNCIDivisions,Centers,andOffices.Thispositionwillberesponsibleforleading,developing,andmaintainingtheeffortsdescribedbelowandcoordinatingactivitieswiththeOfficeofLiaisonActivities(OLA)andtheDirector’sConsumerLiaisonGroup(DCLG)toensuremaximalimpactandauthoritiesfortheseendeavors.Thispositionwillalsointerface,asappropriate,withNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorforassistanceindevelopingtheseefforts.
Inaddition,theDCLGwilltakealeadershiproleincoordinatingtheparticipationofadvocacygroupsandindividualadvocatesinimplementationnotonlyofthisinitiativebutalloftheTRWGinitiatives.Thiswillincludegatheringinputonfundingprioritiesandprogramoperations,recommendingrepresentativesforthevariouscommitteesandworkinggroups,disseminatinginformationonimplementationtothelargerpatientcommunity,andpromotingabetterunderstandingoftheproductiverolesadvocatescanplayintheresearchprocess.
Structured Interactions
OLAwillorganizeregularperiodicmeetingsinvolvingprogramstaffresponsiblefortranslationalresearchfromallNCIDivisions,Centers,andOfficesandrepresentativesfromappropriatefoundationsandadvocacygroupsforthepurposeofaddressingthefullspectrumoftranslationalresearchactivities.Thegoalistoincreaseoverallawarenessandunderstandingofthefullbreadthanddepthoftranslationalresearchinfrastructuresandactivitiesbeingplanned,prioritized,andconductedbybothNCIandfoundationsandadvocacygroups.Thisincludesoutreachandcommunicationprogramsaswellasscientificinfrastructureandresearchprograms,includingSPOREs,theEarlyDetectionResearchNetwork,PhaseI/IIclinicaltrialcontracts,DevelopmentofClinicalImagingDrugEnhancers,RAID,RAPID,cancercenters,etc.Oneadditionalmechanismforenhancinginteractionswillbetoconduct“TranslationalNeedsand
31 NathanDG.Careersintranslationalclinicalresearch—historicalperspectives,futurechallenges.JAMA,2002;287:2424-87.Availableat:http://jama.ama-assn.org/cgi/content/full/287/18/2424#REF-JCO20035-18.
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Opportunities”meetingsconvenedaspartofthenewtranslationalresearchprioritizationprocess(seeCoordinatedManagementInitiativeA4)inassociationwithfoundationoradvocacygroupmeetings.
Participation in NCI Prioritization Process
Advocacygroupsandfoundationshavebuiltstrengthsinscientificreviewandplanning,includingconductingscientificreviewstoinformtheirfundingdecisions.Moreover,aboutone-thirdoftheproposalssubmittedtofoundationsandadvocacygroupsaretranslational.Consequently,representativesfromthesecommunitiescanprovidevaluableinputasNCIprioritizestranslationalresearchprogramsandprojectsacrossthetranslationalresearchenterprise.
Atleastonerepresentativefromafoundationoradvocacygroupactiveintranslationalresearchfundingwillbenamedtoeachyear’sPrioritizationWorkingGroup(seeCoordinatedManagementInitiativeA4).TheadvocacyrepresentativewillbenamedincoordinationwithOLAstaffanddrawnfromthebroadcanceradvocacyandfoundationcommunity.TheselectionprocesswillensurethattheparticipanthasappropriateexpertiseandthattheadvocacycommunityiswellrepresentedinNCI’sprocessesforprioritizingtranslationalresearchopportunities.
Avoidance of Duplicative Review
RepresentativesfromfoundationsandadvocacygroupsindicatethatmanyofthetranslationalresearchproposalssubmittedtotheseorganizationsareeithersimultaneouslysubmittedtoNCIorhavebeenpreviouslyrejectedbyNCI.Consequently,foundations,advocacygroups,andNCIperformduplicativereviewsinmanyinstances.
NCIcannotcoordinatereviewwithanyoutsideagencyorfoundation.However,thereisoneadvocacygroupthatsolicitssummarystatementsfromapplicantswhoarejustoutsidetheNCIpaylineandthenmakesitsfundingdecisionsbasedonthosesummarystatementswithoutconductingaseparatescientificreview.NCIstaffassistinthisprocessbymakingapplicantsawareofthisadditionalfundingopportunity,buttheapplicantmustindependentlypursuethefoundationoradvocacygroupapplicationprocess.ThefeasibilityofextendingthisprocesstoadditionalfoundationsoradvocacygroupswillbeexploredduringtheregularmeetingsbetweenNCIprogramstaffandtheadvocacyorganizations.Ifinterestinthisprocessishigh,OLAwillworkwiththeTranslationalResearchSupportOfficetodevelopanapproachforcommunicatingwithNCIgrantapplicants,foundations,andadvocacygroupsaboutthisoption.
Funding Partnership Development
IncollaborationwiththeTranslationalResearchSupportOfficeanddrawingontheresourcesofNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirector,OLAwillinvestigatethefeasibilityofcreating,throughtheFoundationforNIH,jointfundingopportunities.Thesecouldincludethefollowing:
• Foundation/advocacygroupfundingofacomponentofaSTRAPaward(seeTailoredFundingProgramsInitiativeB3)
• Foundation/advocacygroupfundingofafellowshipforworkinassociationwithaspecifictranslationalresearchprojectembeddedwithinaSTRAP,P01,SPORE,orotheraward
• JointNCIandfoundation/advocacygroupfundingoffellowshipsandothertrainingawards
• Foundation/advocacygroupfundingofaresearchprojectorprogramviatheFoundationforNIH,modeledonprevioussuccessfulexamplessuchastheAVONPartnersforProgressprogram.
Enhanced Outreach Concerning Tissue Donation and Image Collection
Enhancedpublic,patient,andphysicianoutreachemphasizingthecriticalroleoftissuedonationandimagecollectiontocancerresearchprogressisparticularlyimportantastherearegenerallynodirectbenefitstopatientsandnoincentivesforcommunityoncologistswhoreferpatients.Thisisavastlyunderappreciatedaspectofcancerresearch.
StafffromtheTranslationalResearchSupportOfficewillworkwiththeOfficeofEducationandSpecialInitiatives(OESI),theOfficeofCommunications(OC),theOfficeofBiorepositoriesandBiospecimenResearch,andOLAto
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developaproactiveprogramthatinvolvesfoundationsandadvocacygroupsinincreasingoverallpublic,patient,andcommunityoncologistawarenessandunderstandingofthevalueoftissuesampledonationandimagecollectionduringparticipationinclinicaltrialsaswellasduringclinicalfollow-up.OESI,OC,andOLAstaffwilltaketheleadindevelopingthisprogram.AsasimilarinitiativeisbeingpursuedaspartoftheClinicalTrialsWorkingGroupReportimplementation,thisprogramwouldbeoptimallyexecutedintandemwithpublicandpatientoutreachforclinicaltrialparticipation.Asincreasedpublicoutreacheffortsshouldresultinbothincreasedcollectionoftissuesamplesandimagesaswellasincreasedawarenessamongresearchersoftheavailabilityoftheseresources,issuesrelatedtotheownershipandsharingoftheseresourcesmaybecomeincreasinglyprominentandwillneedtobeaddressed.
Thefeasibilityandpotentialeffectivenessofseveralapproachesforoutreachwillbeexplored,includingthefollowing.
1. Assemblecasestudiesthatdemonstratetheimportanceoftissuedonationinadvancingcancerresearchandtreatmentanddistributethroughcancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.
2. DevelopcooperativecommunicationprogramswithsisterFederalagencies,suchastheCentersforDiseaseControlandPreventionandtheOfficeoftheSurgeonGeneral.
3. DevelopinformationalmaterialwithNCI’sCancerInformationServicethatcanbedistributedtopatients,cancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.
4. Compilebestcommunicationpracticesfromcancercentersregardingtissuedonationandimagecollectionanddistributetocancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.
5. FundcommunityresearchprojectsthroughtheClinicalandTranslationalScienceAwardsprogramtodeterminewhyindividualsdoordonotdonatetissuesorimagesforresearchpurposes.
Initialmeetingswillbeconductedwithindividualfoundationandadvocacygroupstoidentifyopportunitiesforeffectivepublicandpatientoutreach.Iftheexploratorymeetingwithanindividualorganizationindicatesthereispotentialforcollaboration,specificactionplanswillbedevelopedforimplementingtheactivitiesandprogramsidentified.NCIwillalsocontactbroad-basedadvocacygroups,suchastheAmericanCancerSociety,theNationalCoalitionforCancerSurvivorship,andtheLanceArmstrongFoundationtoconsiderdevelopingageneralpublicawarenesscampaignonthevalueoftissuesampledonationandimagecollection.Thiscampaignwillutilizemanyofthesamecommunicationtactics,butbeaimedatalargerandmorediverseaudience.
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Initiative C6: Enhance training and career incentives for early translational research.
Rationale
Integrationofawiderangeofdisciplinesfrombothlaboratoryandclinicalresearchinawell-coordinatedteameffortisessentialtoearlytranslation.Thefuturevitalityofthetranslationalresearchenterprisewillthereforedependonanewgenerationofresearcherswhohavemasteredrelevantscientificandclinicaldisciplines,understandboththelaboratoryandclinicalperspective,andareskilledingoal-orientedmanagementofcross-disciplinaryteams.
Initsrecentreportonobstaclestothedevelopmentofnewdrugs,theGovernmentAccountabilityOfficenotedseveralconceptsforimprovingtheproductivityofdrugdevelopmentthatwerehighlightedbyexpertsconsultedforthereport.Amongthesesuggestionswerethefollowingpointsrelevanttoworkforcedevelopment:
Academia could place a greater emphasis on developing research scientists with knowledge of translational medicine by providing financial incentives such as scholarships for students to pursue this discipline. Private and public partnerships could also create these incentives to develop such scientists. One of the panelists suggested that academia, industry, and the FDA (Food and Drug Administration) formally develop a paper that describes the skills most needed by this new type of translational scientist and develop funding and training mechanisms that would specifically support these individuals.32
Currentapproachestofundingandadministrationofbiomedicalresearchandtraininginacademiaoftenpromotethemaintenanceofindependentsilos.Theserelativelyrigidorganizationalelementsnotonlystandinthewayofteamscienceandcross-disciplinaryresearchandtrainingtodaybuttheyalsoretardadaptationtochangesintranslationalscienceforthefuture.ChangesinacademicorganizationalstrategiesandstructurescomplementedwithmoreeffectiveuseofNCIfundingmechanismsfortrainingandincreasedavailabilityofNCIawardprogramsfocusedontranslationalresearchwillbeessentialtodevelopacommittedtranslationalresearchworkforcetomeettherecognizedneedsoftodayandtheemergingneedsoftomorrow.
Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.
Implementation Plan
Translational Research Training Program Announcement
TheCancerTrainingBranchoftheOfficeofCenters,TrainingandResources(OCTR)willdevelopaProgramAnnouncementaddressingtrainingforearlytranslationalresearch.ThePAwilldrawattentiontoopportunitiesfortheuseofexistinginstitutionalfundingmechanisms,suchastheK12,R25T,andT32awards,ascomplementaryelementsinthedevelopmentofintegratedtrainingprogramsfortranslationalresearchersandteams.
Early Translational Research Training Working Group
NCIwillestablishaTranslationalResearchTrainingWorkingGroupundertheauspicesoftheAdvisoryCommitteeandwiththelogisticalsupportoftheTranslationalResearchSupportOffice.TheWorkingGroupwillinclude8-10membersencompassingarangeofkeystakeholders,including:
• TwomembersoftheAdvisoryCommittee
• TheAssociateDirectorforTraining,OCTR
32 NEWDRUGDEVELOPMENT:Science,Business,Regulatory,andIntellectualPropertyIssuesCitedasHamperingDrugDevelopmentEfforts,GAO-0�-49.Washington,DC:GovernmentAccountabilityOffice,November2006,p.36
76 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Operational Effectiveness
• Extramuraltranslationalresearcherswithexperiencerunningformaltranslationalandclinicalresearchtrainingprograms
• Industryrepresentative(s).
TheWorkingGroupwillbeaskedtoreportwithin1yearonthefindingsandrecommendationsderivedfromitsinvestigation,consultation,andconsensus-buildingintheareasdescribedbelow.
Training of Clinician-Scientists for Translational Research. Tomeetthechallengeofensuringacontinualflowofwell-qualifiedresearcherswhocanleadandparticipateinthecomplex,multidisciplinaryresearchactivitiesthatarethefoundationoftranslationalresearch,itisnecessarytodefinetherequiredmixofskillsmoreclearlyandensurethatclinician-scientisttrainingprogramsprovidethoseskillsinamannerthatfacilitatescareerdevelopment.
Toaddressthisissue,theWorkingGroupwillundertakethefollowingtasks:
1. Defineacommonsetofskillsthatqualifyclinician-scientistsforleadershipofandparticipationintranslationalresearchteams;thesearelikelytoincludefoundationalskillsinbasicscience,statisticsandstudydesign,regulatoryaffairs,andmanagementoflarge,complex,multidisciplinaryprojectteams.
2. Reviewexistingclinician-scientisttrainingprogramsandawardstoassesstheextenttowhichtheyprovidetheseskillsandtoidentifygapsandbestpractices.
3. Designamodelcurriculumwithassociatedtrainingstandards,incentives,andbestpracticesthatcanbeusedforcreationofnewtrainingprogramsand/oradaptationofexistingones.
4. Identifyspecificclinicalspecialtiesthatareinadequatelyrepresentedintranslationalresearch.
5. Reviewexistingindustryfellowshipprogramstoassessthescopeofcurrentactivityandidentifybestpractices.
6. Disseminatetheinformationgatheredtothescientificcommunitythroughappropriatepresentationsorpublications.
TheWorkingGroupwillconsultwidelywiththeleadersofexistingclinician-scientisttrainingprograms,NCIstaff,leadersofprofessionalorganizationssuchastheAssociationofAmericanMedicalColleges(AAMC),FDAstaff,andtranslationalresearchleadersfromindustry.
Training of Ph.D. Scientists for Translational Research. ToprovidePh.D.scientistswiththerequisitetrainingtoleadandparticipatemosteffectivelyintranslationalresearch,Ph.D.programsinlaboratorybioscience,publichealth,andbehavioralscienceshouldbeenhancedwithopportunitiestogainafoundationofclinicalknowledge,includingclinicaltrials.
Toaddressthisissue,theWorkingGroupwillundertakethefollowingtasks.
1. DefineacommonsetofskillsthatqualifyPh.D.scientistsforleadershipofandparticipationintranslationalresearchteams;thesearelikelytoincludefoundationalskillsinclinicalmedicineandclinicaltrials,statisticsandstudydesign,regulatoryaffairs,andmanagementoflarge,complex,multidisciplinaryprojectteams.
2. ReviewexistingPh.D.trainingprogramsinlaboratorybioscience,publichealth,andbehavioralsciencetoassessthedegreetowhichtheyprovidetheopportunityforlearningaboutclinicaltopics,regulatoryaffairs,andteammanagement.
3. Identifyapproachesforincorporatingclinicaltopicsintolaboratorybioscience,publichealth,andbehavioralsciencePh.D.programs,includingtakingmedicalschoolcourses.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 77
Report of the NCAB Translational Research Working Group—Operational Effectiveness
4. Identifyspecificscientific,non-M.D.,specialties(includingbiostatistics)thatareinshortsupplyforearlytranslationalresearch.
5. Disseminatetheinformationgatheredtothescientificcommunitythroughappropriatepresentationsorpublications.
TheWorkingGroupwillconsultwidelywiththeleadersofexistingPh.D.programsinlaboratorybioscience,publichealth,andbehavioralscience;NCIstaff;andleadersofrelevantprofessionalorganizations.
Training of Ph.D. Nurses for Translational Research. Translationalresearchwouldbenefitfromtheparticipationofnursingresearcherswhocanlinkdiscoveryresearchonbiologicalmechanismswithnursingresearchinthepatientcareenvironment.Thisparticipationwouldfacilitatetranslationalresearchinitiativesaddressingnewinterventionsforsupportivecareandqualityoflife,aswellastheincorporationofsupportivecareandquality-of-lifedimensionsintotranslationalresearchontherapeuticinterventions.TheWorkingGroupwillconsultwiththeNationalInstituteofNursingResearchtodeterminehowthetwoInstitutescanbestcollaboratetofacilitateappropriatetranslationalresearchtrainingactivities.
Cross-Disciplinary Sharing of Best Practices and Implications of the Clinical and Translational Science Awards (CTSA) Program for Translational Research Training. TheWorkingGroupwillconsultwithrepresentativesofotherbiomedicalresearchdisciplinesandotherNIHInstitutestoidentifyissuesandbestpracticesintranslationalresearchtrainingthatarecommonacrossdisciplines.Inaddition,theWorkingGroupwillconsultwiththeCTSAprogramleadershiponthepotentialimplicationsofCTSAsfortrainingincancer-relatedtranslationalresearch.
Regulatory Affairs Training
TheTRWGidentifiedanacuteneedforgreaterunderstandingoftheFDAregulatoryprocessonthepartofthosewholeadtranslationalresearch.IncollaborationwithFDAandindustry,NCIwillseektoexpandthenumberofshortcourses,intensiveworkshops,sabbaticalfellowshipsinindustry,andothertrainingactivitiesthatcanfitintothecalendarsofactiveclinician-scientistsandprovidetheknowledgeandskillsneededtointeracteffectivelywiththeFDAindruganddevicedevelopment.
Enhancement of Career Support and Incentives
Akeyelementindevelopingarobusttranslationalresearchworkforceistoprovideadequatesupportandincentivestoattractyoungresearcherstoacareerintranslationalscience.Threeapproachesforaddressingthischallengewillbepursued.Thefirstisoptimizingfundingprogramstoencourageandrewardtranslationalresearch.Thesecondaddressesexpandingtheuseofthelegislativesalarycaptoincludetrainingawards.Thethirdistoengageacademicinstitutionsinanactivedialogueconcerningappropriatemodificationstoinstitutionalpracticesthatwillfacilitateacademiccareersintranslationalscience.
Funding Programs and Award Guidelines. TheTRWGhasproposedseveralinitiativesthatwillstrengthentranslationalresearchfundingprograms(seeTailoredFundingProgramsInitiativesB1,B3,andB4).Theguidelinechangesproposedintheseinitiativeswillrewardandencourageprojectsthattakeconceptsthroughdevelopmenttoearlyhumantesting.Theenhancedemphasisintheseprogramsontranslationalresearchasopposedtodiscoverywillprovidegreaterfundingopportunitiesforresearchersprimarilyinterestedinmovingconceptsforwardtoearlyhumantestingratherthansolelyworkingattheinterfaceofdiscoveryandtranslation.TheseprogramscanalsoprovideappropriaterecognitionforinvestigatorsparticipatinginlargecollaborativestudiesbyutilizingtheNIH-widemultipleprincipalinvestigatorand“tetheredawards”conceptsinfundingtheseprograms.Inaddition,guidelinesforcancercenterswillbemodifiedtorewardtheconductoffocusedtranslationalresearchprojectsaswellashigh-quality,investigator-initiated,industry-sponsoredstudies.
78 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Operational Effectiveness
Legislative Salary Cap for Training Awards. NCIleadershipwillworkwithoverallNIHleadershiptomodifyK08,K23,andK24trainingawardstoallowsalarysupportuptothelegislativecap.ThisisinaccordwithRecommendation7oftheAAMC’sTaskForceIIonClinicalResearch(CRTFII)2006reportentitled,“PromotingTranslationalandClinicalScience:TheCriticalRoleofMedicalSchoolsandTeachingHospitals.”33
Academic Reward Practices. NCIandNIHleadershipwillworkproactivelywiththeAAMC,theInstituteofMedicine,andotherorganizationstopersuademedicalschoolandacademicdeansoftheneedtoadjusttheirinstitutions’incentivestructurestorewardcollaborative,multidisciplinarytranslationalresearch.TheNCIwillalsoexaminetheintramuralprogram’sincentivestructurestobesurethatcollaborativetranslationalresearchisproperlyrecognizedandrewarded.TheClinicalTrialsWorkingGroupReportincludedaninitiativetopursuerealignmentofacademicrecognitionpolicies,includingpromotionandtenureguidelines,torewardcollaborativeclinicalresearch.ThiseffortwillbecombinedwiththisnewTRWGproposedefforttorealignthosesamepoliciestorewardcollaborativetranslationalresearchthatmovesdiscoveriestowardearlyhumantesting.Suchchangeswouldrewardacademicsnotonlyforindividualdiscoveryscholarshipbutalsoforadvancingdiscoveriestopatientbenefit.ThisinitiativeparallelsRecommendation6oftheAAMCCRTFIIReport.34
33 ReportoftheAAMC’sTaskForceIIonClinicalResearch.Washington,DC:AssociationofAmericanMedicalColleges,200634 ReportoftheAAMC’sTaskForceIIonClinicalResearch.Washington,DC:AssociationofAmericanMedicalColleges,2006.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 79
Report of the NCAB Translational Research Working Group—Timeline and Budget
Timeline and Budget
Timeline
ImplementationoftheTRWGinitiativesaccordingtotheplansoutlinedinthisreportareprojectedtorequire4to5yearstocomplete,withthefullimpactonroutineNCIoperationalpracticesexpectedtorequireatleast2to3additionalyears.Allinitiativesaretargetedtobeginimplementationbytheendofyearthree.AsummarytimelineispresentedinFigure4andasummarybudgetinFigure5(page80).AscheduleofkeyactivitiesandmilestonesassociatedwitheachinitiativeispresentedinTable1(page83).
Majoritemsforeachyearincludethefollowing:
Year 1
Coordinated Management Initiatives
• EstablishTranslationalResearchSupportOffice.
• ExpandClinicalTrialsAdvisoryCommitteeoversighttoincludetranslationalresearch.
• EstablishTranslationalResearchOperationsCommittee.
• Setinitialtranslationalresearchbudgettarget.
• Establishtranslationalresearchawardcodes.
• EstablishPrioritizationWorkingGroup.
• Initiatefirstannualprioritizationprocess.
• EstablishIndustryRelationsWorkingGroup.
Tailored Funding Program Initiatives
• Modifymultiproject,collaborativeawardguidelines(P50,U-series,etc.).
• DevelopSTRAPawardstructures.
• Establishintegratedreviewproceduresfortranslationalresearchawardsanddevelopmentresourceprograms.
• EstablishIndustryRelationsWorkingGroup.
Operational Effectiveness Initiatives
• Hireprojectmanagementstaff.
• Begintodevelopinventoryofearlytranslationalresearchresources.
• Developprojectmanagementtrainingplan.
• Analyzecoreservicesredundancies.
• BegininteractionswithOfficeofBiorepositoriesandBiospecimenResearchconcerningbiospecimenrepositories.
• Analyzecurrentintellectualpropertyagreements/practices.
• Initiateregularfoundationandadvocacygroupmeetings.
• EstablishTrainingWorkingGroup.
80 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Initiatives FY08 FY09 FY10 FY11 FY12
A1: Integrated NCI Management $800K $800K $850K $850K $850K
A2: Budget Designation — — — — —
A3: Translational Research Coding $150K $150K $150K $150K
A4: Prioritization Process $950K $750K $750K $750K $750K
B1: Modify Translational Research Award Guidelines — — — — —
B2: Improve Investigator-Initiated Translational Research Awards
— — — — —
B3: Special Translational Research Acceleration Project (STRAP) Awards
— — $10M $20M $30M
B4: Academia/Industry Collaboration Awards $5M $10M
B5: Integrated Development Services — — — — —
C1: Project Management $1.35M $1.3M $1.55M $1.75M $2M
C2: Core Services Coordination $200K $370K — — —
C3: Enhance Biorepositories — — — — —
C4: Improve Intellectual Property Negotiations $100K $530K
C5: Enhance Foundation/Advisory Group Collaborations — — — — —
C6: Enhance Training Programs and Career Incentives $300K $100K — — —
Evaluation $350K — $350K — $350K
TOTAL $4.05M $3.99M $13.65M $28.5M $44.1M
Figure 5. TRWG Initiatives Summary Budget
Figure 4. TRWG Initiatives Summary Timeline
Initiatives FY08 FY09 FY10 FY11 FY12A1: Integrated NCI ManagementA2: Budget DesignationA3: Translational Research CodingA4: Prioritization ProcessB1: Modify Translational Research Award Guidelines
B2: Improve Investigator-Initiated Translational Research Awards
B3: STRAP AwardsB4: Academia/Industry Collaboration AwardsB5: Integrated Development ServicesC1: Project ManagementC2: Core Services CoordinationC3: Enhance BiorepositoriesC4: Improve Intellectual Property NegotiationsC5: Enhance Foundation/Advisory Group CollaborationsC6: Enhance Training Programs and Career IncentivesEvaluation
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 81
Report of the NCAB Translational Research Working Group—Timeline and Budget
Year 2
Coordinated Management Initiatives
• Begincodingofnewtranslationalresearchawards.
• Completeretrospectivecodingoftranslationalresearchawards.
• Selectinitialsetoftranslationalresearchpriorities.
Tailored Funding Program Initiatives
• Implementrevisedguidelinesformultiprojectcollaborativeawards.
• IssueinitialSTRAPawardsolicitation.
• Beginintegratedreviewsoftranslationalresearchawardsanddevelopmentofresourceprograms.
Operational Effectiveness Initiatives
• Completeinventoryoftranslationalresearchresources.
• Initiateprojectmanagementtrainingprogram.
• Developcoreservicesdatabase.
• Identifycoreservicesforregionalization.
• Conveneconsensusmeetingsonintellectualpropertyagreements/bestpractices.
• Begininteractionwithacademicandmedicalschooldeansregardingacademicincentives.
• BegintoimplementTrainingWorkingGrouprecommendations.
Year 3
Coordinated Management Initiatives
• Analyzenewlycodedtranslationalresearchportfolio.
• Selectsecondsetoftranslationalresearchpriorities.
Tailored Funding Program Initiatives
• FundinitialSTRAPawards.
• Issueinitialacademic/industrycollaborationawardsolicitation.
Operational Effectiveness Initiatives
• Begintranslationalresearchresourcedatabasedevelopment.
• Conduct2-yearevaluationofprojectmanagementsystem.
• Implementcoreservicesconsolidation,ifappropriate.
• Developharmonizedintellectualpropertyagreements/practices.
• Developagentrepositories/databases,ifappropriate.
82 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Years 4-5
Coordinated Management Initiatives
• Beginmanagingtranslationalresearchportfoliotobudgettarget.
• Continuetoselectannualtranslationalresearchpriorities.
Tailored Funding Program Initiatives
• FundsecondandthirdroundofSTRAPawards.
• Fundfirstandsecondroundofacademic/industrycollaborationawards.
Operational Effectiveness Initiatives
• Completetranslationalresearchresourcedatabasedevelopment.
• Conduct4-yearevaluationofprojectmanagementsystem.
• EstablishcoreservicesRegionalCenters.
Budget
TheestimatedcostsforimplementingtheTRWGinitiativesaccordingtotheplansoutlinedinthisreportarepresentedinTables2and3.Table2presentsthecostsbycategory—Extramural,Analysis/DevelopmentProjects,NCIOperationalActivities,andMeetingSupport.Table3presentsthecostsbyyear.TheestimatedincrementalcostforYear1(FY08)andYear2(FY09)is$4Mannually.TheestimatedcostincreasesinYear3(FY10)to$13.5M,inYear4(FY11)to$28.5M,andinYear5(FY12)to$44Mareentirelyduetoimplementationofnewextramuralfundingprograms.Thus,thesecostincreasesarenottrulyincremental,butrepresentshiftingofasmallfractionofongoingNCItranslationalresearchextramuralfundingintothenewSTRAPandacademic/industrycollaborationawards.
Oftheannual$4Minnonextramuralfundingthroughoutthe5-yearperiod,50%istooperatetheprojectmanagementsystem,25%istosupporttheprioritizationprocess,and25%isfortheNCImanagementandadministrativestructurenecessarytoimplementtheremaininginitiativesandeffectivelyguidethetransformedenterprise.IftheTRWGinitiativesarefullyimplemented,theremaybeadditionalincrementalexpensesthatcannotbeestimatedatthistime.Examplesincludeexpansionoftheprojectmanagementsystemifitissuccessfulanddemandgrows(seeOperationalEffectivenessInitiativeC1)andcreationofagentrepositoriesandassociateddatabasesifthesearedeemedworthwhileandfeasible(seeOperationalEffectivenessInitiativeC4).
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 83
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
veK
ey M
ilest
on
es a
nd
Act
ivit
ies
Co
ord
inat
ed
Man
agem
ent
Year
1(O
ct. 2
007–
Sep
t. 2
008)
Year
2(O
ct. 2
008–
Sep
t. 2
009)
Year
3(O
ct. 2
009–
Sep
t. 2
010)
Year
s 4–
5(O
ct. 2
010–
Sep
t. 2
012)
A1
Inte
gra
ted
NC
I M
anag
emen
t•
Est
ablis
h T
RS
O (
Oct
. 200
7)•
Exp
and
CTA
C o
vers
igh
t (J
an. 2
008)
• E
stab
lish
TR
OC
(Ja
n. 2
008)
• E
stab
lish
Sp
ecia
l P
op
ula
tio
ns
Wo
rkin
g G
rou
p
• Im
ple
men
t re
com
men
dat
ion
s o
f S
pec
ial P
op
ula
tio
ns
Wo
rkin
g G
rou
p
• A
nal
yze
new
ly c
od
ed
po
rtfo
lio (
Oct
. 200
9–M
ar.
2010
)•
Eva
luat
e va
lue
of
con
sort
ia
con
cep
t
• B
egin
man
agin
g p
ort
folio
to
b
ud
get
tar
get
(O
ct. 2
010)
A2:
B
ud
get
D
esig
nat
ion
• S
et in
itia
l bu
dg
et t
arg
et
(Sep
t. 2
008)
• R
evie
w a
nd
co
nfi
rm o
r ch
ang
e b
ud
get
tar
get
• R
evie
w a
nd
co
nfi
rm o
r ch
ang
e b
ud
get
tar
get
• R
evie
w a
nd
co
nfi
rm o
r ch
ang
e b
ud
get
tar
get
A3:
Tr
ansl
atio
nal
R
esea
rch
C
od
ing
• E
stab
lish
co
des
(O
ct.
2007
– M
ar. 2
008)
• A
nal
yze
feas
ibili
ty o
f in
vest
igat
or-
assi
gn
ed c
od
es
• B
egin
co
din
g o
f n
ew
awar
ds
(Oct
. 200
8)•
Co
mp
lete
ret
rosp
ecti
ve
cod
ing
• C
on
tin
ue
anal
ysis
of
feas
ibili
ty o
f in
vest
igat
or-
assi
gn
ed c
od
es
• C
on
tin
ue
cod
ing
of
new
aw
ard
s•
Co
nti
nu
e co
din
g o
f n
ew
awar
ds
A4:
P
rio
riti
zati
on
P
roce
ss•
Est
ablis
h P
rio
riti
zati
on
W
ork
ing
Gro
up
(Ja
n. 2
008)
• D
evel
op
pri
ori
tiza
tio
n
pro
cess
(O
ct. 2
007–
Jan
. 20
08)
• S
olic
it id
eas
(Jan
. 200
8)•
Per
form
lite
ratu
re r
evie
w
(Jan
. –M
ar. 2
008)
• D
evel
op
co
nce
pt
pac
kag
e (A
pr.
–Ju
n. 2
008)
• E
valu
ate
con
cep
ts (
Jul.
2008
)•
Per
form
po
rtfo
lio a
nal
ysis
o
f m
ost
pro
mis
ing
co
nce
pts
(A
ug
.–S
ept.
200
8)
• P
ub
lish
/pre
sen
t p
rio
riti
zed
o
pp
ort
un
itie
s fo
r co
mm
ent
(Oct
. 200
8)•
Sel
ect
init
ial p
rio
riti
es (
Jan
. 20
09)
• In
itia
te F
Y10
pri
ori
tiza
tio
n
pro
cess
(Ja
n. 2
009)
• C
om
ple
te F
Y10
p
rio
riti
zati
on
pro
cess
• S
elec
t an
nu
al p
rio
riti
es
(Jan
. 201
0)•
Init
iate
FY
11 p
rio
riti
zati
on
p
roce
ss (
Jan
. 201
0)
• C
on
tin
ue
ann
ual
p
rio
riti
zati
on
pro
cess
• S
elec
t an
nu
al p
rio
riti
es
(Jan
. 201
1 an
d J
an. 2
012)
Tab
le 1
. Im
ple
men
tati
on
Tim
elin
e
84 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
veK
ey M
ilest
on
es a
nd
Act
ivit
ies
Tailo
red
Fu
nd
ing
P
rog
ram
sYe
ar 1
(Oct
. 200
7–S
ept.
200
8)Ye
ar 2
(Oct
. 200
8–S
ept.
200
9)Ye
ar 3
(Oct
. 200
9–S
ept.
201
0)Ye
ars
4–5
(Oct
. 201
0–S
ept.
201
2)
B1:
M
od
ify
Tran
slat
ion
al
Res
earc
h A
war
d
Gu
idel
ines
• R
evis
e g
uid
elin
es•
Exa
min
e re
view
pan
els
• Im
ple
men
t re
vise
d
gu
idel
ines
• C
on
tin
ue
gu
idel
ine
revi
sio
n
if n
eces
sary
• C
on
tin
ue
to im
ple
men
t re
vise
d g
uid
elin
es•
Per
form
ro
llin
g r
evie
w
eval
uat
ion
• C
on
tin
ue
to im
ple
men
t re
vise
d g
uid
elin
es•
Imp
lem
ent
rolli
ng
rev
iew
if
app
rop
riat
e
B2:
Im
pro
ve
Inve
stig
ato
r-In
itia
ted
Tr
ansl
atio
nal
R
esea
rch
A
war
ds
• E
xam
ine
stu
dy
sect
ion
s•
Beg
in N
IH-w
ide
dia
log
ue
• C
on
tin
ue
NIH
-wid
e d
ialo
gu
e•
Co
nti
nu
e N
IH-w
ide
dia
log
ue
B3:
S
pec
ial
Tran
slat
ion
al
Res
earc
h
Acc
eler
atio
n
Pro
ject
(S
TR
AP
) A
war
ds
• D
evel
op
ST
RA
P a
war
d
stru
ctu
res
(Jan
.–S
ept.
200
8)•
Co
nti
nu
e to
dev
elo
p S
TR
AP
aw
ard
str
uct
ure
s (O
ct.–
Dec
. 20
08)
• P
rep
are
init
ial S
TR
AP
so
licit
atio
n (
Jan
.–M
ar. 2
009)
• Is
sue
ST
RA
P s
olic
itat
ion
(A
pr.
2009
)•
Rev
iew
ST
RA
P a
pp
licat
ion
s (J
ul.–
Sep
t. 2
009)
• Is
sue
firs
t S
TR
AP
aw
ard
s (J
an. 2
010)
• Is
sue
seco
nd
an
d t
hir
d
rou
nd
of
ST
RA
P a
war
ds
(Jan
. 201
1 an
d 2
012)
B4:
A
cad
emia
/In
du
stry
C
olla
bo
rati
on
A
war
ds
• E
stab
lish
Ind
ust
ry R
elat
ion
s W
ork
ing
Gro
up
• P
rep
are
acad
emic
/ind
ust
ry
colla
bo
rati
on
so
licit
atio
n
(Oct
. –D
ec. 2
009)
• Is
sue
solic
itat
ion
(Ja
n. 2
010)
• R
evie
w a
pp
licat
ion
s (A
pr.–
Jun
. 201
0)
• Is
sue
firs
t aw
ard
s (O
ct.
2010
)•
Issu
e se
con
d r
ou
nd
of
awar
ds
(Oct
. 201
1)
B5:
In
teg
rate
d
Dev
elo
pm
ent
Ser
vice
s
• E
stab
lish
inte
gra
ted
rev
iew
p
roce
du
res
• B
egin
inte
gra
ted
rev
iew
s•
Eva
luat
e p
ote
nti
al f
or
assa
y/m
ole
cula
r an
alys
is d
evic
e d
evel
op
men
t p
rog
ram
• C
on
tin
ue
inte
gra
ted
rev
iew
s•
Co
nti
nu
e in
teg
rate
d r
evie
ws
Tab
le 1
. Im
ple
men
tati
on
Tim
elin
e (c
on
tin
ued
)
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 85
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
veK
ey M
ilest
on
es a
nd
Act
ivit
ies
Op
erat
ion
al
Eff
ecti
ven
ess
Year
1(O
ct. 2
007–
Sep
t. 2
008)
Year
2(O
ct. 2
008–
Sep
t. 2
009)
Year
3(O
ct. 2
009–
Sep
t. 2
010)
Year
s 4–
5(O
ct. 2
010–
Sep
t. 2
012)
C1:
P
roje
ct
Man
agem
ent
• H
ire
pro
ject
man
agem
ent
TR
SO
sta
ff
mem
ber
(O
ct. 2
007)
• B
egin
to
dev
elo
p in
ven
tory
of
reso
urc
es•
Rev
ise
gu
idel
ines
• D
evel
op
tra
inin
g p
lan
• B
egin
liai
son
wit
h P
50/U
-ser
ies
pro
gra
m
staf
f (A
pr.
2008
)•
Hir
e D
ivis
ion
al p
roje
ct m
anag
emen
t st
aff
• C
on
tin
ue
to e
stab
lish
in
ven
tory
of
reso
urc
es•
Imp
lem
ent
revi
sed
g
uid
elin
es•
Init
iate
tra
inin
g p
rog
ram
• B
egin
res
ou
rce
DB
d
evel
op
men
t*•
Co
nti
nu
e to
im
ple
men
t re
vise
d
gu
idel
ines
• C
on
tin
ue
trai
nin
g
pro
gra
m•
Co
nd
uct
2-y
ear
eval
uat
ion
• C
on
tin
ue
reso
urc
e D
B
dev
elo
pm
ent
• C
on
tin
ue
to
imp
lem
ent
revi
sed
g
uid
elin
es•
Co
nti
nu
e tr
ain
ing
p
rog
ram
• C
on
du
ct 4
-yea
r ev
alu
atio
n
C2:
C
ore
Ser
vice
s C
oo
rdin
atio
n•
An
alyz
e co
re s
ervi
ces
red
un
dan
cies
• R
evis
e g
uid
elin
es•
Beg
in t
o d
evel
op
co
re s
ervi
ces
dat
abas
e
• C
on
tin
ue
to d
evel
op
co
re
serv
ices
dat
abas
e•
Iden
tify
ser
vice
s fo
r re
gio
nal
izat
ion
• D
evel
op
co
nso
lidat
ion
p
lan
s, a
s ap
pro
pri
ate
• Im
ple
men
t co
nso
lidat
ion
• Im
ple
men
t re
gio
nal
izat
ion
, as
app
rop
riat
e
• C
on
tin
ue
to
imp
lem
ent
con
solid
atio
n•
Co
nti
nu
e to
im
ple
men
t re
gio
nal
izat
ion
C3:
E
nh
ance
B
iore
po
sito
ries
• R
evis
e g
uid
elin
es•
Beg
in in
tera
ctio
ns
wit
h O
BB
R/B
CC
•
Co
nti
nu
e in
tera
ctio
ns
wit
h O
BB
R/B
CC
• C
on
tin
ue
inte
ract
ion
s w
ith
OB
BR
/BC
C•
Co
nti
nu
e in
tera
ctio
ns
wit
h O
BB
R/B
CC
C4:
Im
pro
ve
Inte
llect
ual
P
rop
erty
N
ego
tiat
ion
s
• A
nal
yze
curr
ent
agre
emen
ts/p
ract
ices
• C
on
ven
e co
nse
nsu
s m
eeti
ng
s•
An
alyz
e al
tern
ate
IP
mo
del
s•
An
alyz
e re
po
sito
ry
op
tio
ns
• D
evel
op
har
mo
niz
ed
agre
emen
ts/p
ract
ices
• D
evel
op
ag
ent
rep
osi
tori
es/
dat
abas
es, i
f ap
pro
pri
ate
• C
on
tin
ue
to d
evel
op
ag
ent
rep
osi
tori
es/
dat
abas
es, i
f ap
pro
pri
ate
C5:
E
nh
ance
Fo
un
dat
ion
/A
dvi
sory
Gro
up
C
olla
bo
rati
on
s
• In
itia
te r
egu
lar
fou
nd
atio
n a
nd
ad
voca
cy
gro
up
mee
tin
gs
o A
void
du
plic
ativ
e re
view
o E
xplo
re f
un
din
g p
artn
ersh
ips
o B
egin
ou
trea
ch f
or
tiss
ue
do
nat
ion
• C
on
tin
ue
and
exp
and
in
tera
ctio
ns
• Im
ple
men
t id
enti
fied
in
itia
tive
s
• C
on
tin
ue
and
exp
and
in
tera
ctio
ns
• Im
ple
men
t id
enti
fied
in
itia
tive
s
• C
on
tin
ue
and
exp
and
in
tera
ctio
ns
• Im
ple
men
t id
enti
fied
in
itia
tive
s
C6:
E
nh
ance
Tr
ain
ing
P
rog
ram
s an
d C
aree
r In
cen
tive
s
• D
evel
op
tra
inin
g P
A (
Oct
. 200
7 –M
ar. 2
008)
• E
stab
lish
Wo
rkin
g G
rou
p (
Jan
. 200
8)•
Co
nd
uct
Wo
rkin
g G
rou
p d
elib
erat
ion
s (J
an.–
Sep
t. 2
008)
• A
nal
yze
reg
ula
tory
tra
inin
g o
pti
on
s (A
pr.–
Sep
t. 2
008)
• W
ork
wit
h N
IH le
ader
ship
co
nce
rnin
g
leg
isla
tive
cap
in t
rain
ing
aw
ard
s
• C
om
ple
te W
ork
ing
Gro
up
d
elib
erat
ion
s (D
ec. 2
008)
• B
egin
to
imp
lem
ent
WG
re
com
men
dat
ion
s•
Beg
in in
tera
ctio
n w
ith
ac
adem
ic d
ean
s/A
AM
C/
IOM
reg
ard
ing
aca
dem
ic
ince
nti
ves
• C
on
tin
ue
to
imp
lem
ent
Wo
rkin
g G
rou
p
reco
mm
end
atio
ns
• C
on
tin
ue
inte
ract
ion
w
ith
aca
dem
ic d
ean
s/A
AM
C/IO
M r
egar
din
g
acad
emic
ince
nti
ves
• C
on
tin
ue
to
imp
lem
ent
Wo
rkin
g G
rou
p
reco
mm
end
atio
ns
• C
on
tin
ue
inte
ract
ion
w
ith
aca
dem
ic d
ean
s/A
AM
C/IO
M r
egar
din
g
acad
emic
ince
nti
ves
Eva
luat
ion
Imp
lem
enta
tio
n o
f T
RW
G in
itia
tive
s•
Dev
elo
p e
valu
atio
n s
yste
m•
Co
nd
uct
bas
elin
e ev
alu
atio
n•
Co
nd
uct
2-y
ear
eval
uat
ion
• C
on
du
ct 4
-yea
r ev
alu
atio
n
*Fu
rthe
rde
velo
pmen
tof
core
ser
vice
sda
taba
se(
Initi
ativ
eC
2).
Tab
le 1
. Im
ple
men
tati
on
Tim
elin
e (c
on
tin
ued
)
86 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
veE
xpen
ses
Co
ord
inat
ed
Man
agem
ent
Ext
ram
ura
lA
nal
ysis
/Dev
elo
pm
ent
Pro
ject
sN
CI O
per
atio
nal
A
ctiv
itie
sM
eeti
ng
Su
pp
ort
Tota
l
A1
Inte
gra
ted
NC
I M
anag
emen
t
N/A
Po
rtfo
lio A
nal
ysis
Yr
3–5
......
......
.....
$50K
/yr
Tran
slat
ion
al R
esea
rch
S
up
po
rt O
ffice
*
Yr
1–5
.....
......
...$7
00K
/yr
Wo
rkin
g G
rou
p
Mee
tin
gs
Yr
1–5
......
......
...$1
00/y
r
Yr
1 ...
......
......
....$
800K
Yr
2 ...
......
......
....$
800K
Yr
3 ...
......
......
....$
850K
Yr
4 ...
......
......
....$
850K
Yr
5 ...
......
......
....$
850K
A2:
B
ud
get
D
esig
nat
ion
N/A
N/A
See
No
te 1
N/A
See
No
te 1
A3:
Tr
ansl
atio
nal
R
esea
rch
C
od
ing
N/A
N/A
RA
EB
Sta
ff
Yr
2-5 .
......
......
.. $
150K
/yr
N/A
Yr
1 ...
......
......
......
..$0
Yr
2 ...
......
......
....$
150K
Yr
3 ...
......
......
....$
150K
Yr
4 ...
......
......
....$
150K
Yr
5 ...
......
......
....$
150K
A4:
P
rio
riti
zati
on
P
roce
ss
N/A
Pri
ori
tiza
tio
n W
ork
ing
G
rou
p S
up
po
rt
(Lit
erat
ure
rev
iew
, p
ort
folio
an
alys
is, e
tc.)
Yr
1 ...
......
......
....$
400K
Yr
2-–5
.....
......
...$2
00K
/yr
Tran
slat
ion
al R
esea
rch
S
up
po
rt O
ffice
Yr
1–5
......
......
...$3
50K
/yr
Pri
ori
tiza
tio
n W
ork
ing
G
rou
p M
eeti
ng
s
Yr
1–5
......
......
...$2
00K
/yr
Yr
1 ...
......
......
....$
950K
Yr
2 ...
......
......
....$
750K
Yr
3 ...
......
......
....$
750K
Yr
4 ...
......
......
....$
750K
Yr
5 ...
......
......
....$
750K
No
te 1
: In
clu
ded
in T
ran
slat
ion
al R
esea
rch
Su
pp
ort
Off
ice
exp
ense
s fo
r In
itia
tive
A1
(see
ab
ove
).
*Expandedmanagem
entandprofessionalstafffortheTranslationalR
esearchSupportO
fficeoftheCoordinatingCenterforClinicalTrials,includingclerical,officeexpenses,
travel,etc.TheproratedTranslationalR
esearchSupportO
fficestaffandoperatingexpensesformanagingtheprioritizationandprojectm
anagem
entsystemsarenotincluded
inth
eto
tals
how
n;th
ese
expe
nses
are
incl
uded
inth
eex
pens
esf
orI
nitia
tive
A4
and
Initi
ativ
eC
1,r
espe
ctiv
ely.
Tab
le 2
. Est
imat
ed Im
ple
men
tati
on
Bu
dg
et b
y C
ateg
ory
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 87
Report of the NCAB Translational Research Working Group—Timeline and Budget
Tab
le 2
. Est
imat
ed Im
ple
men
tati
on
Bu
dg
et b
y C
ateg
ory
(co
nti
nu
ed)
Init
iati
veE
xpen
ses
Tailo
red
Fu
nd
ing
P
rog
ram
sE
xtra
mu
ral
An
alys
is/D
evel
op
men
t P
roje
cts
NC
I Op
erat
ion
al
Act
ivit
ies
Mee
tin
g S
up
po
rtTo
tal
B1:
M
od
ify
Tran
slat
ion
al
Res
earc
h A
war
d
Gu
idel
ines
N/A
N/A
See
No
te 1
N/A
See
No
te 1
B2:
Im
pro
ve
Inve
stig
ato
r-In
itia
ted
Tr
ansl
atio
nal
R
esea
rch
A
war
ds
N/A
N/A
See
No
te 1
N/A
See
No
te 1
B3:
S
pec
ial
Tran
slat
ion
al
Res
earc
h
Acc
eler
atio
n
Pro
ject
(S
TR
AP
) A
war
ds
Yr
3 ...
......
......
......
$10M
Yr
4 ...
......
......
......
$20M
Yr
5 ...
......
......
......
$30M
N/A
See
No
te 2
N/A
Yr
1 ...
......
......
......
.$ 0
Yr
2 ...
......
......
......
.$ 0
Yr
3 ...
......
......
......
$10M
Yr
4 ...
......
......
......
$20M
Yr
5 ...
......
......
......
$30M
B4:
A
cad
emia
/In
du
stry
C
olla
bo
rati
on
A
war
ds
Yr
4 ...
......
......
......
.$ 5
M
Yr
5 ...
......
......
......
$10M
N/A
See
No
te 1
N/A
Yr
1 ...
......
......
......
.$ 0
Yr
2 ...
......
......
......
.$ 0
Yr
3 ...
......
......
......
.$ 0
Yr
4 ...
......
......
......
.$ 5
M
Yr
5 ...
......
......
......
$10M
B5:
In
teg
rate
d
Dev
elo
pm
ent
Ser
vice
sN
/AN
/AS
ee N
ote
1N
/AS
ee N
ote
1
No
te 1
: In
clu
ded
in T
ran
slat
ion
al R
esea
rch
Su
pp
ort
Off
ice
exp
ense
s fo
r In
itia
tive
A1
(see
pag
e 86
).
No
te 2
: In
clu
ded
in p
rio
riti
zati
on
pro
cess
exp
ense
s (I
nit
iati
ve A
4, s
ee p
age
86).
88 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
veE
xpen
ses
Op
erat
ion
al
Eff
ecti
ven
ess
Ext
ram
ura
lA
nal
ysis
/Dev
elo
pm
ent
Pro
ject
sN
CI O
per
atio
nal
A
ctiv
itie
sM
eeti
ng
Su
pp
ort
Tota
l
C1:
P
roje
ct
Man
agem
ent
N/A
Trai
nin
g A
nal
ysis
Yr
1 ...
......
......
......
......
..$5
0K
Res
ou
rce
Inve
nto
ry
Yr
1–2
......
......
......
..$2
00K
/yr
Res
ou
rce
Dat
abas
e D
evel
op
men
t*
Yr
3–5
......
......
......
..$2
00K
/yr
Eva
luat
ion
Yr
3 ...
......
......
......
......
$250
K
Yr
5 ...
......
......
......
......
$250
K
Tran
slat
ion
al R
esea
rch
S
up
po
rt O
ffice
Yr
1–5
......
......
......
..$3
50K
/yr
Div
isio
nal
Pro
ject
M
anag
ers
Yr
1–3
......
......
......
.$75
0K/y
r
Yr
4–5
......
......
......
.$1.
2M/y
r
N/A
Yr
1 ...
......
......
......
...$1
.35M
Yr
2 ...
......
......
......
...$1
.30M
Yr
3 ...
......
......
......
...$1
.55M
Yr
4 ...
......
......
......
...$1
.75M
Yr
5 ...
......
......
......
...$2
.00M
C2:
C
ore
Ser
vice
s C
oo
rdin
atio
n
N/A
Co
re S
ervi
ces
An
alys
is
Yr
1 ...
......
......
......
......
$200
K
Co
re S
ervi
ces
Init
ial
Dat
abas
e D
evel
op
men
t
Yr
2 ...
......
......
......
......
$250
K
See
No
te 1
Reg
ion
aliz
atio
n W
ork
ing
G
rou
p M
eeti
ng
Yr
2 ...
......
......
......
......
$120
K
Yr
1 ...
......
......
......
......
$200
K
Yr
2 ...
......
......
......
......
$370
K
Yr
3 ...
......
......
......
......
...$
0K
Yr
4 ...
......
......
......
......
...$
0K
Yr
5 ...
......
......
......
......
...$
0K
C3:
E
nh
ance
B
iore
po
sito
ries
N/A
N/A
See
No
te 1
N/A
See
No
te 1
C4:
Im
pro
ve
Inte
llect
ual
P
rop
erty
N
ego
tiat
ion
s
N/A
IP A
gre
emen
t A
nal
ysis
Yr
1 ...
......
......
......
......
$100
K
Alt
ern
ate
IP M
od
els
An
alys
is
Yr
2 ...
......
......
......
......
$200
K
An
alys
is o
f R
epo
sito
ry
Op
tio
ns
Yr
2 ...
......
......
......
......
$200
K
See
No
te 1
Co
nse
nsu
s M
eeti
ng
s
Yr
2 ...
......
......
......
......
$120
K
Yr
1 ...
......
......
......
......
$100
K
Yr
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rthe
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le 2
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ple
men
tati
on
Bu
dg
et b
y C
ateg
ory
(co
nti
nu
ed)
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 89
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
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ses
Op
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le 2
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ed Im
ple
men
tati
on
Bu
dg
et b
y C
ateg
ory
(co
nti
nu
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90 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Timeline and Budget
Init
iati
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xpen
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et b
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ar
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 91
Report of the NCAB Translational Research Working Group—Evaluation and Outcome Measures
Evaluation and Outcome Measures
Introduction
Formalevaluationisanintegralpartofeffectiveprogramorenterprisemanagement.Itprovidesarationalbasisforassessingtherelationshipbetweenthestrategiesandtacticsimplementedinaprogramandtheirefficacyinachievingthedesiredgoalsandforidentifyingappropriatecorrectiveactionifneeded.
TheinitiativesproposedbytheTRWGrecognizetheimportanceofevaluationinthecontextofactivities,suchasearlytranslationalresearch,thatarestronglygoaloriented.Theintroductionofmilestone-basedprojectmanagementforcomplexprojectssuchasthosesupportedbytheproposedSTRAPawardsbringsevaluationdowntotheprojectlevelanddeploysitasatooltoincreaseproductivity.AcomparableevaluativedisciplinemustbeappliedtomeasuringtheeffectoftheTRWGinitiativesonthetranslationalresearchenterpriseasawholeinordertoensureeffectiveuseofthescarceresourcesentrustedtoit.
Evaluationattheprogramorenterpriselevelshouldaddressbothprocessandoutcomes.Processassessmentisimportantinordertohaveconfidencethattheeffortisproceedingappropriatelyduringitsinitialphase,aswellastocreateabasisforchartingarevisedcourseofactionifneeded.Outcomesassessmentisessentialtoconfirmthattheeffortisachievingitsgoals.
Evaluationoftranslationalresearchprogramspresentsseveralchallenges.First,importantdimensionsofperformancecannotbefullycapturedusingpurelyobjectiveandquantitativemeasures.Themeasuresmustincludeajudiciousblendofqualitativeandquantitative,objectiveandsubjectivemeasures.Second,althoughtranslationalresearchisstronglygoaloriented,itsresultsneverthelessremainsomewhatunpredictable,andcandependtoasignificantdegreeonfactorsbeyondthecontroloftheparticipants.Andthird,translationalresearchisacomplexsysteminwhichmultipleinternalandexternalfactorsinteractinmanydifferentways—someobservable,andsomenot—toaffectoutcomes.Thus,attributionofobservedoutcomestoparticularpolicies,organizationalstructures,ormanagementdecisionscanbedifficult.
Use of Measures
Anevidence-basedapproachisessential.Thedeterminationofsuccessorfailureanddecisionsonanyneededcoursecorrectionswillnotbeautomaticormechanical,butamatterofjudgmentbyexpertsinthefield.However,thisexpertjudgmentmustbeinformedbysystematic,structuredempiricaldatasothattherewillbeasharedbasisfordiscussionanddecision-making.Themeasuresuseddonotserveasthesumtotaloftheevaluation,butasessential“rawmaterial”foralargerprocessofexpertjudgmentinwhichthebroadoncologyresearchcommunitymustparticipate.
Theneededmeasuresfallintothreecategories:
• ProgrammanagementprocessmeasuresthatevaluateimplementationoftheinitiativesrecommendedbytheTRWG
• Systemprocessmeasuresthatevaluatetheeffectofthechangesinoperationalprocessesoncoordination,prioritization,management,funding,andconductoftranslationalresearch
• Systemoutcomemeasuresthatassesstheintendedresult—anincreasednumberofnewtreatments,diagnosticmethods,etc.,thatare“handedoff”tomiddleandlate-stagetrialsfordefinitiveevaluation.
Toevaluatetheimpactoftheproposedinitiatives,itisessentialtoconductabaselineevaluationofselectedmeasurespriortoimplementation.Onlythencantheeffectofchangeberecognized.Itisalsoessentialtosetrealistictimelinesforachievementoftheobjectivessothatevaluationisnotattemptedeithertooearlyortoolateintheprocess.Forexample,certainprocessmeasuresmayberelevantonlyafterotherprocessesonwhichtheydependhavebeencompleted.Similarly,itmaybeamatterofyearsbeforeitisreasonabletoexpectcertainoutcomestobeapparent.Nevertheless,manyprocessmeasurescanbefruitfullyassessedatintervalstodocumenttheprogressoftheinitiatives.
92 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Evaluation and Outcome Measures
Aswell-definedmeasuresdonotcurrentlyexistformanyelementsoftheNCItranslationalresearchenterprise,establishingspecificmeasureswillbeanongoinganditerativeprocess.NCIwillengageexperiencedevaluationspecialiststoassistindevelopmentofthesemeasuresaswellasthesurveyinstruments,statisticaladjustments,andothertoolsrequiredtoconducttheevaluationsandrendertheevaluationmeasurespracticalandvalid.ThesespecialistswillalsoworkwithNCItodeterminetheappropriatetimingforexaminingthevariousmeasuresbasedonimplementationtimelinesandtheimpactsenvisioned.Abaselineevaluationofrelevantelementsofthecurrentsystemwillbeconductedassoonaspossibletoprovideareliablebasisforascertainingthevalueoftheinitiatives.Theresultsofthisbaselineevaluationwillbeanalyzedtodeterminewhetherthechosenmeasuresarevalidorshouldbeeliminatedorrevised.
Categories of Measures
Program Management Process Measures
ThesemeasureswillbetrackedbyNCIonacontinuingbasisaspartofitsmanagementofinitiativeimplementationandwillbeassessedinlightoftheproposedimplementationplanandtimeline.Questionstobeaddressedinclude:
• Werethetasksinitiatedontime?
• Didtheyfollowtheimplementationplanasoutlined?
• Ifobstacleswereencountered,werealternateplansimplementedquicklyandeffectively?
• Werethetasksaccomplishedontimeorweretimelinesrevisedinatimelyandrealisticfashion?
System Process Measures
Theproposedinitiativeshavethreekeyprocessobjectives:
• Improvedcoordinationandmoreactive,goal-oriented,andtransparentmanagementofthetranslationalresearchenterprise
• Moreeffectivetailoringoffundingprogramstothespecificcharacteristicsandneedsoftranslationalresearch
• Enhancedoperationalefficiencyandeffectivenessoftranslationalresearchprojectsandthemanysupportingactivitiesthatareessentialtotheenterprise.
Inaddition,theseimprovementsareexpectedtoencouragegreaterinterestandinvolvementintranslationalresearchbyinvestigators.Thus,afourthprocessobjectivecanbeadded:
• Increasedtranslationalresearchactivity.
Toaccomplishtheseobjectives,theproposedinitiativesenvisionimplementingnewstructures,processes,andbehaviorsonthepartofparticipantsintheenterprise.Thesystemprocessmeasuresmustthereforeprovideempiricalevidenceofwhetherthenewstructuresandprocessesareeffective,whetherthetargetedbehaviorsarechangingintheintendedways,whetherthelevelofactivityisincreasing,andwhethertheimpactedcomponentsandthesystemasawholeareinfactbecomingmorecoordinated,morecollaborative,moretransparent,moregoaloriented,moreefficient,andmoreproductive,aswellasbettermanagedandbetterprioritized.Measuresshouldalsobeincludedtoverifythatthenewobjectivesarenotachievedattheexpenseofothervaluedcharacteristicsofthetranslationalresearchenterpriseasitexiststoday.
Someofthesystemcharacteristicscanbeassessedviaobjectivemeasures,whileothersmustbeassessedsubjectively,throughasystematicandtransparentprocessofsolicitingexpertopinion.Itisimportanttorememberthatnosinglemeasurewillprovideaconclusiveindicatorofsuccess,norabasisforattributionofcauseandeffect.Rather,each
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 93
Report of the NCAB Translational Research Working Group—Evaluation and Outcome Measures
measuremustbecombinedwiththeothersandincludedinalarger,comprehensiveevaluationbyabroadrangeofcriticalstakeholders.
System Outcome Measures
ThemostimportantandmeaningfuloutcomemeasuresforevaluatingthesuccessoftheTRWGinitiativeswillbethosethatassesstheextenttowhichthereisanincreasednumberofnewcancertreatments,diagnosticmethods,andotherinterventionsadvancedtomiddle-andlate-stagetrials.
Inpractice,however,developmentoftenoccursonverylongtimescale—aslongasadecadeormore.Inevaluatingprogramsthatarecharacterizedbysuchlongtimescales,itiscommontoincludeproxyoutcomemeasuresaswell.Suchproxymeasurescapturecertaincriticalaspectsofsystemactivity,andassuchcouldalsobeviewedasprocessmeasures.However,iftheproxymeasuresaresufficientlytightlylinkedtotheultimatedesiredoutcome,theycanconstituteausefulinterimguidetoprogress.
Proposedsystemoutcomemeasureswillthereforeincludethefollowing:
• Numberofnewtherapies,diagnostic/screeningtests,lifestylealternations,preventiveagents,etc.,thatsuccessfullycompleteNCI-supportedearly(PhaseIorII)humantestingandarejudgedsuitableforlate-stagetesting
• Numberofnewtherapies,diagnostic/screeningtests,etc.,handedofftoindustryforfurtherdevelopmentfromanypointinthedevelopmentalpathway
• Numberofnewtherapies,diagnostic/screeningtests,lifestylealternations,preventiveagents,etc.,underNCI-supporteddevelopmentaccordingtooneoftheTRWGdevelopmentalpathways(proxymeasure).
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 95
Report of the NCAB Translational Research Working Group—Appendices
Appendices
Appendix A: Foundational Documents
Appendix B: TRWG Translational Research Definition and Scope of Activity
Appendix C: TRWG Developmental Pathways to Clinical Goals
Appendix D: Translational Research Portfolio for the NCI Translational Research Working Group
Appendix E: Process Analysis for the NCI Translational Research Working Group
Appendix F: TRWG Meeting Dates
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 97
Report of the NCAB Translational Research Working Group—Appendix A
Appendix A: Foundational Documents
FoodandDrugAdministration.InnovationorStagnation:ChallengeandOpportunityontheCriticalPathtoNewMedical
Products,March2004.
http://www.cancer.gov/pdf/trwg/Critical-Path-whitepaper.pdf
NationalCancerAdvisoryBoard.AdvancingTranslationalCancerResearch:AVisionoftheCancerCenterandSPORE
ProgramsoftheFuture,ReportoftheP30/P50AdHocWorkingGroup,February2003.
http://deainfo.nci.nih.gov/advisory/ncab/p30-p50/P30-P50final12feb03.pdf
NationalCancerAdvisoryBoard.CancerataCrossroads:AReporttoCongressfortheNation,Reportofthe
SubcommitteetoEvaluatetheNationalCancerProgram,September1994.
http://www.cancer.gov/pdf/trwg/Cancer-at-a-Crossroads.pdf
NationalCancerAdvisoryBoard.RestructuringtheNationalCancerClinicalTrialsEnterprise,ReportoftheClinical
TrialsWorkingGroup,June2005.
http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf
NationalCancerInstitute.ReportoftheKidney/BladderCancersProgressReviewGroup,August2002.
http://planning.cancer.gov/pdfprgreports/2002kidneyreport.pdf
NationalCancerInstitute.ReportoftheLeukemia,Lymphoma,andMyelomaProgressReviewGroup,May2001.
http://planning.cancer.gov/pdfprgreports/2001llm.pdf
NationalCancerInstitute.ReportoftheLungCancerProgressReviewGroup,August2001.
http://planning.cancer.gov/pdfprgreports/2001lung.pdf
NationalCancerInstitute.ReportoftheSarcomaProgressReviewGroup:ARoadmapforSarcomaResearch,January
2004.
http://planning.cancer.gov/pdfprgreports/2004sarcoma.pdf
NationalCancerInstitute.ReportoftheStomach/EsophagealCancersProgressReviewGroup,December2002.
http://planning.cancer.gov/stomach/stomach_esophageal.pdf
NationalInstitutesofHealth.NIHRoadmapforMedicalResearch,Re-engineeringtheClinicalResearchEnterprise,
October2006.
http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp
ThePresident’sCancerPanel.TranslatingResearchintoCancerCare:DeliveringonthePromise,2004-2005Annual
Report,NationalInstitutesofHealth,NationalCancerInstitute,June2005.
http://deainfo.nci.nih.gov/ADVISORY/pcp/pcp04-05rpt/ReportTrans.pdf
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 99
Report of the NCAB Translational Research Working Group—Appendix B
Appendix B: TRWG Translational Research Definition and Scope of Activity
“Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence,
morbidity, and mortality.”
The Translational Continuum*
Basic Science Discovery
Early Translation Late Translation Dissemination Adoption
• Promising molecule or gene target
• Candidate protein biomarker
• Basic epidemiologic finding
• Partnerships and collaboration (academia, government, industry)
• Intervention development
• Phase I/II trials
• Phase III trials• Regulatory approval• Partnerships• Production and
commercialization• Phase IV trials
– approval for additional uses
• Payment mechanism(s) established to support adoption
• Health services research to support dissemination and adoption
(newdrug,assay,device,behavioralintervention,educationalmaterial,training)• To community
health providers• To patients and
public
• Adoption of advance by providers, patients, public
• Payment mechanism(s) in place to enable adoption
TRWG Activity
*FromthePresident’sCancerPanel’s2004-2005reportTranslatingResearchIntoCancerCare:DeliveringonthePromise.
New Tools and New Applications
Lab
Clinic Population
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Transforming Translation—Harnessing Discovery for Patient and Public Benefit 101
Report of the NCAB Translational Research Working Group—Appendix C
Appendix C: TRWG Developmental Pathways to Clinical Goals
Introduction to the TRWG Developmental Pathways
TheTRWGhasconstructedsix“developmentalpathways”thatcharacterizethetransformationofscientificdiscoveriesintonewclinicalmodalitiesforoncology.Thesemodalitiesfallintotwofundamentalandcomplementarycategories:
Riskassessmentmodalities,intendedtocharacterizethecancer-relatedhealthstatusofanindividual:
• Biospecimen-basedriskassessmentdevices(protocols,reagents,instruments,etc.)
• Image-basedriskassessment(agentsortechniques).
Interventivemodalities,intendedtochangethecancer-relatedhealthstatusofanindividual,viapreventionortreatment:
• Agents(drugsorbiologics)
• Immuneresponsemodifiers(vaccines,cytokines,etc.)
• Interventivedevices
• Lifestylealterations.
Thedevelopmentalpathwaydiagramsoutlinetheprocessesthroughwhichfundamentalscientificdiscoveriesaretransformedintotheseclinicalmodalities.Thediagramsspecifykeyactivitiesanddecisionpointsalongthedevelopmentpath,clarifydependenciesamongdifferentstepsaswellaskeyeventsthatoccurinparallel,andshowimportantfeedbackloopsanditerativeprocessesthatareembeddedwithinthedevelopmentprocess.
TheprimarypurposeofthesepathwaysistofacilitateTRWGdiscussionsbyclarifyingcertainessentialcharacteristicsoftheearlytranslationprocess.TRWGmembershaveusedthemtohelpunderstandthechallengesfacedbytranslationalresearchersandtoidentifywaystohelpthetranslationalresearchprocessfunctionmoreeffectively.Forexample,thepathwaydiagramsstimulatedfruitfuldiscussionamongTRWGmembersandparticipantsinthefirstTRWGpublicroundtableaboutrelationshipsamongdifferentelementsofthetranslationalresearcheffort,resourcesneeded,andbarriersthatstandinthewayofmorerapidprogress.
Increatingthesepathways,theTRWGwasawarethatsuchidealizedrepresentationscannotcapturethefullcomplexityoftherealworld.Foreachactivity,decisionpoint,parallelpath,orfeedbackloop,itisunderstoodthattherearemanymorevariationsthatcanoccur—andindeedhaveoccurred—inpracticeandthatnotallstepsmayoccurineachinstance.Inaddition,thesediagramsdonotcapturethefullrangeofpossibleinteractionsbetweenthepathways,nordotheyaddressthewaysinwhichinsightsgainedfromlate-stageclinicaltrialscaninfluencethedevelopmentprocess.Finally,therehasbeennoattempttoaddresstheinfluenceofmarketconditions,projectedfinancialreturn,orreimbursementconsiderationsondevelopmentpathwaydecisionsmadeinthecommercialsector.
Tofacilitateunderstandingofthepathways,agenericpathwaytemplatewasalsocreatedwhichcapturesthecommonelementsofthepathwaysinsimplifiedform.Thegenericpathwayappliesequallytoboththeriskassessmentandtheinterventivemodalities.Notethat,forinterventions,someofthesupportingtoolsrequiredinthedevelopmentprocess(redboxintheright-handsequenceofthegenericpathway)arethemselvesriskassessmentmodalities.
102 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix C
Discovery with potential clinical application
Redirect researcheffort elsewhere
no
Fundamental research
no
yes
Does envisioned clinicalneed justify expenditure of resources?
yes
GenericDevelopmental
Pathway
ClinicalModalities
forOncology
NCI TRWGversion 060807
Box = ActionBox/Ellipse = Iterative Action
Diamond = Decision
noIs the empirical basis for
attributing clinical relevance convincing?("credentialed concept")
yes
Develop modality
Efficacy justifycontinued development?
Refine for safety /manufacturability /
deployability
no
yes
Early-stageclinical trials
Refine modalityfor efficacy
no
Applicablestandards
met?Can it
be fixed?
no
Is development processlikely to be feasible?
Decision to proceed
Supporting tools
Creation of modality
Preclinical development
Develop requiredsupporting tools
or systems
Clinical Trials
Dec
isio
nto
proc
eed
Supp
ortin
gto
ols
Cre
atio
nof
mod
ality
Prec
linic
alde
velo
pmen
tCl
inic
altri
als yes
Assesstarget
effects
Identify cohortthat would
benefit
Generic Developmental Pathway: Clinical Modalities for Oncology
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 103
Report of the NCAB Translational Research Working Group—Appendix C
Discovery of molecular biomarker with clinical potential
Redirect researcheffort elsewhere
no
Fundamental research
no
no
yes
Develop reproducibleassay and standard
reagent(s) forbiomarker or profile
Is it feasible to developthe protocol / reagent / device?
yes
Does envisioned clinicalneed justify expenditure of resources?
DevelopmentalPathway
Biospecimen-BasedRisk Assessment
Devices(Protocols / Reagents /
Instruments)
Biomarkers forScreening,
Diagnosis, Staging,Response Assessment,Prognosis, Prediction
NCI TRWGversion 020607
Box = ActionDiamond = Decision
no
yes
Validate assay and correlation of biomarker withoutcome retrospectively using a large number
of specimens in different labs
Develop /refineclinical grade
biomarker assayprotocol / reagent / device
Validate correlation ofbiomarker with outcome as
a primary or secondary endpointin a prospective human study
Human study of utility ofbiomarker to direct
therapy or chemopreventionor predict outcome / risk
Is correlationstatistically robust?
yes
no
Is correlationstatistically robust?
yes
Can itbe fixed?
no
yes
no Outcome =Disease occurrenceDisease progressionResponse to therapy
Biomarker =Single gene / protein
Molecular profile
Sensitivity and specificityexpected to be sufficient for clinicalutility? ("credentialed biomarker")
Is correlationstatistically robust?
yes
no
Define patient subset withbiomarker using assayon a limited number of
specimensin a single lab
Identify or developbiospecimenrepositorieslinked with
outcomes data
Biospecimen-Based Risk Assessment Devices (Protocols, Reagents, Instruments, etc.)
104 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix C
Redirect researcheffort elsewhere
yes
Does envisioned clinicalneed justify expenditure of resources?
DevelopmentalPathway
Image-BasedRisk AssessmentAgent / Technique
Biomarkersfor Screening,
Diagnosis, Staging,Response Assessment,Prognosis, Prediction
NCI TRWGversion 041707
Box = ActionDiamond = Decision
yes
Fundamental / applied research
Discovery of imaing biomarker with clinical potential
yes
Does theagent requireradiolabeling?
Optimize acquisitionand analyticparameters
in preclinical orPhase 0 setting
Performradiolabeling,dosimetry, etc.
Preclinicalperformanceadequate?
Can itbe fixed?
no no
yes
agentyes
no
yes
Pre-IDE meeting forplatform if necessary
Clinicalperformanceadequate?
Can itbe fixed?
no
Establish GMP manufacturingif necessary
yes
yes
no
Clinical study requiredfor regulatory approval?
Optimized platform availablefor clinical testing,
file 510(k) if necessaryFile IDE if necessary,
perform study
Regulatoryapproval
yes
Phase II+ trialsfor specific
clinical utilities
no
Test / refine imagingperformance, PK/PD,
toxicology, etc. inpreclinical setting
Test / refine imagingperformance, PK/PD,
toxicology, etc. inPhase I/II setting
Does new or optimizedexisting system or platform need
regulatory approval?
Establish GMP productionfor agent if necessary
Submit INDif necessary
no
yes
Is it feasible to develop theagent or imaging technique?
Is there an existing imaging platformfor the agent or technique?
Develop necessary newimaging platform
(iterative with development ofagent / technique)
technique
Is the innovationan agent or
a technique?
no
Sensitivity and specificityexpected to be sufficient for clinical utility?
("credentialed biomarker")
no
no
no
yes
Image-Based Risk Assessment (Agents or Techniques)
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 105
Report of the NCAB Translational Research Working Group—Appendix C
Discovery of target with clinical potential
Redirect researcheffort elsewhere
no
Fundamental research
Develop and validateassay and standardreagents or imaging
biomarkers to measurebiological response*
no
yes
Implement experimentalsystem to assess impact
of perturbing target
Does influencingtarget decrease oncogenic
activity?
yes
no
Identify candidateagents and screen forbinding and influence
on activity
Toxicity acceptable?Can itbe fixed?
no
yes
Identify or developreproducible assay
for effect on oncogenicactivity
Identify marker(s)that define(s)patient subset
with target
Characterize statisticalcorrelation of markerswith outcomes, select
optimal marker orprofile
Is correlationclinicallyrelevant?
Validate assay orimaging biomarker
for identifyingpatient cohort
yes
no
Is the empirical basis forattributing clinical potential alone and/or
in combination convincing?("credentialed target")
Is it feasible to identify/develop an agent against the target?
yes
Does envisioned clinicalneed justify expenditure of resources?
yes
Activity / PK justifycontinued development?
yes
no
DevelopmentalPathway
Agent(Drug or Biologic)
for
Therapy or Prevention
NCI TRWGversion 020607
Box = ActionBox/Ellipse = Iterative Action
Diamond = Decision
no
Identify or developclinically- or target-
relevant cellculture system
and/or animal model
Select most promisingcandidates... Refine structure
based on random modification /screening or structure-based design... Assesscombinations...Identify
lead candidate
Conduct initial toxicology screenDevelop and
validate assay andstandard reagents orimaging biomarkers
to measuremolecular endpoint
in humans*
Identify or developbiospecimen /
image repositorieslinked with
outcomes data
Identify or developreproducible assay
and standard reagentsor imaging biomarkers
for target*
no
Agents (Drugs or Biologics) page 1 of 2
106 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix C
Process development / Pilot manufacturing
Implement GLP / GMP manufacturing
Definitive toxicityacceptable?
Submit IND
Phase I / IIClinical Trials
Verify activity / PK
Verify activity / PK / stability / QC
Conduct definitive toxicology screen
yes
yes
yes
no
yes
Activity / PK preserved?Can itbe fixed?
yes
no
Can itbe fixed?
Activity / PK / stability/ QC OK?
no
yes
no
no
*see Biospecimen RADand Imaging Pathways
Agents (Drugs or Biologics) page 2 of 2
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 107
Report of the NCAB Translational Research Working Group—Appendix C
Redirectresearch
effort elsewhere
no
Fundamental research
no
Measure response toimmune response modifier
yes
Process development / Pilot manufacturingand scale-up
yes
Does envisioned clinicalneed justify expenditure of resources?
yes
DevelopmentalPathway
ImmuneResponse Modifiers
(Vaccines,Cytokines, etc.)
for
Therapyor Prevention
NCI TRWGversion 020607
Box = ActionDiamond = Decision
no Is the empirical basis for attributingclinical potential convincing?
("credentialed immune modifier")
Measure response toimmune response modifier
Can itbe fixed?
nono
Lead immune response modifier candidate
Is it feasible to identify/develop an immune response modifier?
Identify ordevelop
delivery vehicle(vector, cell, etc.)
Characterizeand/or modify
antigen(s)
Develop immuneresponse modifier
Activity sufficient towarrant continued development?
Refinedeliveryvehicle
Refineantigen(s)
yes
yes
Refineimmunemodulator
Activity sufficient towarrant continued development?
Identify or developclinically-relevant
cell culture systemand/or animal model
no
Refine immuneresponse modifier
and / orimmunization strategy
Discovery of antigen or other immune modifierwith clinical potential in specific cancer(s)
Identify or developimmune modulator(adjuvant,cytokine,chemokine, etc.)
Identifypatient subsetwith immune
target
Characterize statisticalcorrelation of target
with outcomes
Is correlationclinicallyrelevant?
Identify ordevelop
reproducibleassay andstandard
reagents orimaging
biomarkersfor immune
target*
Identify ordevelop
biospecimen /image
repositorieslinked withoutcomes
data
Develop andvalidate assayand standardreagents or
imagingbiomarkers to
measuremolecularendpoint
in humans*
Develop/validateassay and standard
reagents orimaging biomarkers
to measureresponse
to immuneresponse modifier*
no
yes
Validateassay orimaging
biomarkers foridentifying
patient cohort
Immune Response Modifiers (Vaccines, Cytokines, etc.) page 1 of 2
108 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
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Implement GLP / GMP manufacturing
Submit IND
Phase I / IIClinical Trials
Activity preserved?
Verify activity
Can itbe fixed?
nono
Verify activity
Activity preserved?Can itbe fixed?
nono
yes
yes
yes
Note: This pathway is designed to accommodate immuneresponse modifiers of two types: "simple" (such as a cytokine useddirectly as a therapeutic agent) and "composite" (such as a vaccinethat incorporates an antigen, a vector and an immune modulator).For simple agents, the extra boxes that are incorporated in thediagram to capture parallel development of the components of
a composite product may be ignored.
*see Biospecimen RAD and Imaging Pathways
Conduct toxicology screen
yes
Toxicityacceptable?
yes
no
Immune Response Modifiers (Vaccines, Cytokines, etc.) page 2 of 2
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 109
Report of the NCAB Translational Research Working Group—Appendix C
Technology innovation or innovativeapplication of existing technology
Redirect researcheffort elsewhere
no
no
no
yes
Is it feasible to developthe technology?
yes
Does envisioned clinicalneed justify expenditure of resources?
DevelopmentalPathway
InterventiveDevice
NCI TRWGversion 020607
Box = ActionDiamond = Decision
yes
Test on phantomsand / or animals
Define usageprotocol for humans
Build / refine clinical-grade device
Phase I trials(proof of principle)
Does technologyfunction as intended?
yes
Analyze technologyutility in laboratory
Fundamental / applied research
Is the empirical basis forattributing clinical potential convincing?
("credentialed technology")
Build / refineprototype
device
Can itbe fixed?
no
yes
no
Regulatory submission
Test on phantomsand / or animals
Does technologyfunction as intended?
yes
Can itbe fixed?
no
yes
"Phase zero"tests on humans
Identify marker(s)that define(s)patient subset
with target
Characterize statisticalcorrelation of markerswith outcomes, select
optimal marker orprofile
Is correlationclinicallyrelevant?
Validate assay orimaging biomarker
for identifyingpatient cohort
no
Identify or developbiospecimen /
image repositorieslinked with
outcomes data
yes
Identify or developreproducible assay
and standard reagentsor imaging biomarkers
for target*
Develop and validateassay and standardreagents or imaging
biomarkers to measurebiological response*
Develop andvalidate assayand standardreagents or
imagingbiomarkersto measuremolecularendpoint
in humans*
*see Biospecimen RAD and Imaging Pathways
no
Interventive Devices
110 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix C
Discovery of correlation between behavior or exposure and disease
Redirect researcheffort elsewhere
no
yes
yes
DevelopmentalPathway
LifestyleAlteration
NCI TRWGversion 041707
Box = ActionDiamond = Decision
Does lifestyle alterationhave intended effect?
yes
Laboratory / epidemiological research
Is empirical basis for attributingcausal effect consistent across diverse
populations and study designs?("credentialed discovery")
Can itbe fixed?
nono
Identify correspondinghuman
lifestyle alteration
Identify targetpopulation via
existing databasesor new studies
Pilot studyto assess
effectiveness oflifestyle alteration
Study of effectivenessin larger, more
diverse population
Refinelifestyle
alteration
yes
yes
no
Evaluateeffect in
animal model
Develop and validatebiochemical,
behavioral and/orimaging "assays"to measure effect
of lifestyle alteration*
This diagram is intended to characterize the identification ordevelopment of lifestyle alterations that address behaviors(e.g., tobacco use, dietary patterns, sun / UV exposure)
or environmental exposures (e.g., toxic chemicals)associated with cancer.
*see Biospecimen RAD and Imaging Pathways
Is there arelevant animal model?
Does envisioned clinicalneed justify expenditure of resources?
Can a specific lifestylealteration be identified that
would mitigate the risk factor?
yes
no
no
Lifestyle Alterations
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 111
Report of the NCAB Translational Research Working Group—Appendix D
Appendix D: Translational Research Portfolio for the NCI Translational Research Working Group
Introduction and Summary
TheNationalCancerInstitute(NCI)supportsresearchthatspansbasicthroughclinicalinvestigations.Specificresearchawardsmaypredominantlyaddressbasicresearch,translationalresearch,clinicalresearch,oracombination.TheNCI’sfiscalyear2004researchportfoliowasanalyzedtounderstandtheInstitute’soveralleffortintranslationalresearch,informthedeliberationsoftheNCITranslationalResearchWorkingGroup(TRWG),andserveasapilotforfutureeffortsatanalyzingtranslationalresearch.ThisdocumentpresentsthemethodsusedforidentifyingNCI’stranslationalresearchawardsandprogramsandthesummarizedresultsoftheanalysis.
Key Findings
1. Theportfolioanalysisidentifiedawardsvaluedat$1.3billion(relativetoatotalNCIresearchbudgetof$4.4billioninFY20041)thatfittheinclusioncriteriafor“translationalresearch”(seesubsequentdiscussionforspecificcriteria).Asthecriteriawereappliedexpansively—includingas“translational”allawardsthathadanytranslationalcomponent—theportfoliolikelyoverestimatesthevalueofNCI-sponsoredtranslationalresearch.Amoredetailedassessmentofasampleof65R01awardsforthedegreeoftheirtranslationalresearchrelevance(seepage114,ValidityofTranslationalResearchFundingEstimate)suggeststhatthisestimateofoverallfundingfortranslationalresearchmaybehighby20-40%.
2. Awardsidentifiedas“translational”aredistributedthroughouttheInstitute.AllNCIaward-sponsoringOffices,Centers,andDivisionsfundtranslationalresearch,tovaryingdegrees(Figures1A,1B,and1C).
3. Awardsidentifiedas“translational”aredistributedacrossmanydifferentfundingmechanismstovaryingdegrees(Figures2A,2B,and2CandTables1and2).Approximatelythesamedollarvalueof“translational”fundsisawardedthroughprogramandcooperativeawardmechanismsandthroughindividualresearchawards.
4. Themajorityof“translational”fundsareawardedtoinstitutionswithNCI-designatedcancercenters(Figures3Aand3B).ThepercentageofNCIfundingidentifiedas“translational”atbothinstitutionswithNCI-designatedcancercentersandthosewithoutthemissimilar(Figure3C).
Methodology
Criteria for Including Awards as “Translational Research”
ThescopeofactivityoftheTRWGcanbedefinedas“earlytranslation”basedonthecontinuumdevelopedbythePresident’sCancerPanel.2Withthisandtheinterestincapturingthebroadestpossiblelandscapeinmind,criteriaweredefinedtoidentifyawardstobeincludedintheanalysis.Anawardabstractthatmetatleastoneoftheinclusioncriteriaforasinglespecificaimwasconsidered“translational,”evenifasignificantportionoftheproposedworkdidnotmeetthecriteria.Generally,awardswereidentifiedas“translationalresearch”basedontheawardabstractproposingtoconductresearchthatwouldresultinmovingadiscoveryalongthepathwaytoadefinedclinicalgoalorproductaccordingtothebench-to-bedsidemodel,includingusingclinicalresearchresultstoguidebasiclaboratorystudies.Ifanawardabstractdidnotmeetanyoftheinclusioncriteria,theawardwasnotconsideredtranslational.
Thefollowingcriteriawereusedtoidentifyawardstobeincludedintheportfolio:
1 “FactBook,”NationalCancerInstitute,2004,pageB-2.Availableat:http://fmb.cancer.gov/financial/04Factbk.pdf.ThetotalNCIbudgetinFY2004was$4.�billion,fromwhichthe$329millionfor“ProgramManagementandSupport”wasexcluded.
2 http://deainfo.nci.nih.gov/advisory/pcp/pcp04-05rpt/ReportTrans.pdf.
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• Studiesofagents,includingchemical,biological,immunologic,imaging,etc.,atanystagefromevaluatingtheagentinrelevantmodelsystemsthroughPhaseIIclinicaltrials
• Studiesofmarkersandassaystomeasuretheefficacyofanagentorinterventivedevice,atanystagefromdevelopmentofanassaytotestingforclinicalutilityinpreclinicalandclinicalstudies
• StudiesofinterventivedevicesanywherealongthecontinuumfrombuildingacompleteprototypedevicetotestingadeviceinPhaseIIclinicaltrialsinhumans
• Studiesofbiomarkersandassaysfordetection,diagnosis,prognosis,andpredictionanywherealongthepathfromepidemiologicfindingstoatrialoftheclinicalutilityofthemarkerinhumans
• Studiesofimagingdevicesanywherealongthecontinuumfrombuildingacompleteprototypedevicetotestingtheclinicalutilityofthedeviceinhumans
• Endogenous(e.g.,geneticandmolecular)andexogenous(e.g.,viral,dietary,environmental)epidemiologicstudiesinvolvingasamplepopulationofatleast150cases
• Awardsthatincludethecreationorexpansionofrepositoriesofcohortdataand/orspecimenbanks
• Lifestyle,dietary,orbehavioralstudiesthatdevelopandvalidateortestaninterventionforcancercontroland/orpreventionpurposes(e.g.,tobaccousecessation,changestodiet/exercise,increasedparticipationincancerscreening)
• “Bedside-to-bench”studiesinwhichresultsfrompreclinicalandclinicalstudiesofagentsanddevicesareusedtoenhancethecapacitiesoftheagentsordevices,includingtheevaluationofbasicmechanismsnewlyinspiredbythepreclinicalorclinicalstudies
• Awardsforcorefacilitiesandsharedresourcesinvolvedintranslationalresearch
• AwardsthatproposetoconductPhaseIand/orPhaseIIclinicaltrials
• PhaseIIIclinicaltrialawardsthatincludeacorrelativeresearchcomponent.
Thefollowingareexamplesoftypesofawardsthatwerenotconsidered“translational”—awardsthatfellonlyintothesecategorieswereexcludedfromthetranslationalresearchportfolio:
• Discoveryormechanisticstudies
• Studiesdesignedentirelytodevelopamodel,whetherbiologic,population,statistical,orothertype
• Small-scale,hypothesis-generatingepidemiologystudies
• Developmentoftoolstoenablebasicorclinicalresearch(e.g.,computersoftware,nonclinicalassays,enhancementstoproteomics/arrays)
• Late-phaseclinicaltrials,withnoindicationofcorrelativecomponents
• Surveillance,survivorship,andoutcomesresearch
• Studiestodevelopcomponentsofnewdevices/assaysbutnottodevelopacompleteprototypedeviceorassay
• Developmentofeducationalmaterialsforcareprovidersorgeneralcancereducationalmaterials—materialsnotdirectlyintendedtochangeabehaviortocontrolorpreventcancer
• Studiesthatreferencelong-termtranslationalgoalssubsequenttothecurrentgrantfundingperiod
• Awardsforwhichtheabstractisambiguousorunavailable.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 113
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Data Collection
TheanalysiswasbasedonallawardsactiveinFiscalYear2004ascontainedintheCancerResearchPortfoliodatabasesystem.3
Analyzingresearchprojectsrequireseitherusingdatafromanestablishedcodingsystemorevaluatingresearchprojectabstractstoclassifytheprojects.Translationalresearchisnotcapturedinanyofthecodesappliedtogrants,suchasSpecialInterestCategory(SIC)orNIHClinicalAspect(NIHCA)codes;therefore,individualprojectabstractswereevaluatedtoidentifythetranslationalgrants.Projectswerefilteredtolimittheanalysistothesubsetoftheportfoliomostlikelytoincludetranslationalresearchprojects.Asetoffundingmechanismsandinitiativeprogramswasentirelyincludedintheanalysisduetothefocusedtranslationalnatureoftheprograms(e.g.,SpecializedProgramsofResearchExcellence[SPOREs],SmallBusinessInnovationResearch[SBIR]/SmallBusinessTechnologyTransfer[STTRs],RapidAccesstoInterventionDevelopment[RAID]).Forotherfundingmechanisms,theNIHCA4codewasusedtofiltertheprojectstoanalyzeonlythosewith25%-100%clinicalaspect.Otherfundingmechanismswereentirelyexcludedduetoeithertheunavailabilityofabstracts(e.g.,contractawardssuchastheN01mechanism)ortheiremphasisonnonresearchgoals(e.g.,trainingandeducationawardssuchasT32andR25).
Thefollowingawardcategorieswereincludedwithoutreviewofabstractsorspecificapplicationoftheinclusioncriteriadueto(1)thelackofdetailinprojectabstractsandtheperceptionthatthesearetranslational,and(2)theinclusionofPhaseIandIIclinicaltrialsastranslationalresearch:
• AllClinicalandComprehensiveP30CancerCenters(butnoBasicCancerCenters)
• AllK12mechanismclinicaloncologyresearchcareerdevelopmentawards
• AllprojectsoftheRAIDandDrugDevelopmentGroup(DDG)programs,sponsoredbytheNCI’sDevelopmentalTherapeuticsProgram
• AllprojectsoftheRapidAccesstoPreventiveInterventionDevelopment(RAPID)program,sponsoredbytheNCI’sDivisionofCancerPrevention.
Inthefollowingawardcategories,abstractswerereviewedfortranslationalcomponentsaccordingtotheinclusionandexclusioncriteria:
• Allawardsfundedthroughthefollowinginitiatives:SpecializedProgramsofResearchExcellence,EarlyDetectionResearchNetwork(EDRN),MouseModelsofHumanCancersConsortium(MMHCC),NetworkforTranslationalResearch:OpticalImaging(NTROI),In VivoCancerMolecularImagingCenters(ICMICs),andIntegrativeCancerBiology(ICB)
• AllPhase1andPhase2SBIRandSTTRawards(mechanismsR41,R42,R43,andR44)
• Allintramuralresearchawards(CenterforCancerResearch[CCR]and“Parent”DivisionofCancerEpidemiologyandGenetics[DCEG])
• R24andU24Corefacilityawards.
3 TheCancerResearchPortfolio(CRP)isapublicWebsitewithinformationoncancerresearchandfundingopportunitiesgatheredfromtheNIH-wideInformationforManagement,Planning,Analysis,andCoordination(IMPACII).TheCRPismanagedthroughtheNCIOfficeofSciencePlanningandAssessment.
4 NIHCAcodesarequartile-basedmeasures,assignedbyNCI’sResearchAnalysisandEvaluationBranch(RAEB),oftherelevanceofprojectstotheNIHdefinitionofclinicalresearch.NIHdefineshumanclinicalresearchasfollows:(1)Patient-orientedresearch.Researchconductedwithhumansubjects(oronmaterialofhumanoriginsuchastissues,specimens,andcognitivephenomena)forwhichaninvestigator(orcolleague)directlyinteractswithhumansubjects.Excludedfromthisdefinitionarein vitrostudiesthatutilizehumantissuesthatcannotbelinkedtoalivingindividual.Patient-orientedresearchincludes:(a)mechanismsofhumandisease,(b)therapeuticinterventions,(c)clinicaltrials,or(d)develop-mentofnewtechnologies.(2)Epidemiologicandbehavioralstudies.(3)Outcomesresearchandhealthservicesresearch.
114 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
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Inthefollowingawardcategories,onlyawardswith25%-100%NIHCAcodeswerereviewedfortranslationalcomponentsaccordingtotheinclusionandexclusioncriteria:
• K01,K05,K07,K08,K22,K23,andK24careerdevelopmentawards
• P01,P20,R01,R03,R21,R33,R37,U01,U19,U54,andU56awards.
AwardscodedastranslationalwerestratifiedusingthesponsoringDivision,thecommonscientificoutline(CSO)codes,andtheinstitutionswheretheresearchgrantsareheldtoidentifypatternsoftranslationalresearchprojects.Forexample,researchinstitutionswereaggregatedintothreecategoriesbasedontheavailableinstitutionaldata.Alltranslationalintramuralawardswerecollectedinonecategory,andthetranslationalextramuralawardsweredividedintotwocategories—thosewheretheresearchgrantswereheldatclinicalandcomprehensiveNCI-designatedcancercentersandthosewherethegrantswereheldatotherinstitutions(includingbasiccancercenters).
Assessment of Inclusion Criteria—P01/R01 Analysis
TogaininsightintothevalidityoftheclassificationsystemforP01andR01awards,twoanalyseswereundertaken.First,NCIprogramdirectorsidentifiedawardsintwogroups:translationalandnottranslational.TheyidentifiedatotalofsevenP01awardsastranslationaland11P01awardsasnottranslational.Foreachoftheseawards,theclassificationassignedbytheprogramdirectorswascomparedwiththeclassificationofthesesameawardsintheoriginalportfolioanalysisbasedonreviewoftheabstracts.Inthisexercise,sixofthesevenP01awardsidentifiedastranslationalbytheprogramdirectorshadalsobeencodedastranslationalduringtheoriginalportfolioanalysis.Moreover,9ofthe11P01awardsidentifiedasnottranslationalbytheprogramdirectorshadalsobeencodedasnottranslationalduringtheoriginalportfolioanalysis.
Second,asetof36R01awardsactiveinFY2004wereidentifiedbyTRWGmembersastranslationalawards.Theclassificationoftheseawardsbasedonabstractreviewduringtheoriginalportfolioanalysiswasasfollows:
• Thirtyawardshadbeenclassifiedastranslational.
• Twoawardshadbeenclassifiedasnottranslational.
• Fourawardswerenotincludedintheabstractreviewbecausetheyhada0%NIHCAcode.
TheseresultsindicatethattheinclusioncriteriawerereasonablyaccurateinidentifyingawardsthatwouldbeconsideredtranslationalbyNCIprogramdirectorsandTRWGmembers.
Validity of Translational Research Funding Estimate
Togaininsightintotheaccuracyofthetranslationalresearchfundingestimate(seeTable1),100randomlyselectedawardsfromthelistofR01awardsclassifiedastranslationalintheoriginalportfolioanalysiswereevaluatedfortheextenttowhichtheyweretrulytranslationalbasedonspecificaims.Ofthe100awards,65weredeterminedtohaveabstractsthatclearlyidentifiedspecificaims.Eachofthese65awardabstractswasreviewedasecondtimetoassesstheextentoftranslationalresearchrelevanceandassignedatranslationalscoreaccordingtothepercentofthespecificaimsthatwereconsideredtranslational.Ofthe65awardsreviewed,40receivedtranslationalscoresof76%-100%,eightreceivedscoresof51%-75%,13receivedscoresof26%-50%,andtworeceivedscoresof1%-25%.Theremainingtwoprojectspreviouslyidentifiedastranslationalbasedontheoriginalabstractreviewwereconsideredtohavenotranslationalcomponentsinthissecondreview.Applyingthesetranslationalscorestocalculateaweightedaverageoftranslationalcharacterforthissetofawardssuggeststhattheoverallestimateoffundsattributabletotranslationalactivitymaybeoverstatedbyapproximately20-40%.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 115
Report of the NCAB Translational Research Working Group—Appendix D
Findings: Translational Research Awards by Award Category
Table1(page11�)summarizesbymechanismtheawardscodedas“translational.”Themechanismsarealsogroupedbyawardcategory.Thesecondcolumnidentifiesthenumberofactiveawardsidentifiedas“translational”accordingtothecriteriadiscussedearlier.ThethirdcolumnidentifiesthetotalnumberofactiveawardsinthatmechanisminFY2004.Thefourthcolumnistheresultofdividingcolumn2bycolumn3,toshowthepercentageofawardsinthatmechanismidentifiedastranslational.ThefifthcolumnshowsanestimateofthetotalfundinginFY2004fortheawardscodedastranslational.
“Awardsforcorefacilitiesandsharedresourcesinvolvedintranslationalresearch”wasoneoftheinclusioncriteriaemployed.Thatcriterionidentifiedasetofawardmechanismsthatfundresearchinfrastructure,includingtheCancerCenters(P30mechanism)andR24andU24awards.Astheseinfrastructureawardsmaybeusedforpurposesspanningbasic,translational,andclinicalresearch,theywereseparatedfromthosemechanismsintendedtofundtranslationalresearchprojects.TheseinfrastructureawardsaresummarizedinTable2(page118).Itwasalsonotedthatmanyofthecollaborativeresearchmechanisms(e.g.,P01,andP50)alsofundcorefacilitiesasonefacetoftheoverallaward.Therefore,thesecorefacilitieswereevaluatedforthedegreetowhichtheysupportedtranslationalresearch,andtheresultsareincludedinTable2.
Future Considerations for Translational Research Analysis: Recommended Improvements in Award Coding System to Facilitate More Accurate Analysis of Translational Research Portfolio
Whentheportfolioanalysisexercisewasprepared,itrevealedthattherewasnoexistingcodingsystemthatcapturedtranslationalresearch;theTRWGthereforedevelopedanadhocsystemtosupportitsdeliberations.Theadhocsystemwaslabor-intensivetoapplyandresultedinasetoffindingsthatsomeTRWGmembersfoundtobecounterintuitive(especiallytheoverallsizeoftheenterpriseandthesubstantialamountoftranslationalresearchconductedunderindividualinvestigatorawards).Managingtranslationalresearchmoreeffectivelyinthefuturerequiresamorelogisticallystraightforwardandpreciselydefinedmethodforcodingawardsastranslationalresearch.Tothatend,thefollowingrecommendationsaremade.
1. New coding methods need to be developed to identify, classify, and categorize “translational research.” AsshowninFigure4,awardsidentifiedas“translational”aredistributedacrossNCI’sCSOcodes.Figures5Aand5Bshowthatawardsidentifiedas“translational”aredistributedacrossNIHCAcodesaswell.Moreover,analysisoftheR01awardsdesignatedastranslationalbyTRWGmemberssuggeststhatthe0%NIHCAcodealsocontainssometranslationalprojects.Figure5BsuggeststhatNIHCAcodesareapartiallyeffectivefilter,however,asthelikelihoodofbeingidentifiedas“translational”increasedfromtheNIHCA25%quartiletothe�5%quartile.5Thedifficultyinusingstandardcodingmechanismsinclassifyingresearchas“translational”or“nottranslational”suggeststhatnewmechanismsneedtobedevelopedtoidentify,classify,andcategorize“translationalresearch.”Itwillbeimportanttocodeseveralspecificaspectsoftranslationalresearch(e.g.,studypopulationbyorgan,stageofcancerdevelopment,intendedclinicalgoal(s)—riskassessmentdevice,interventionagent,interventiondevice,immunologicintervention,lifestylemodification,andmechanisticpathwayunderinvestigation)inaconsistentmanner.
2. Precise definitions of translational research and subcomponents of translational research and specific examples of both translational and nontranslational awards will be required as part of developing any new coding process. OperationalizingtheTRWG’sinclusioncriteriafortranslationalresearchproveddifficultevenwhenindividualawardabstractswerereviewed.However,theexercisesperformedtoassesstheinclusioncriteriasuggestthatreviewofabstracts,thoughlaborious,resultedinjudgmentsconsistentwiththoseofscientistscloselyassociatedwiththeindividualprojects.
5 Figure5C,however,showsthatonly1%ofNCIawardsactiveinFY2004wereclassifiedasbeinginthe�5%NIHCAquartile.
116 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix D
3. A database needs to be created that completely and accurately collects the current status of core facilities and infrastructure, captures their total dollar value or number, and allocates their usage to basic, translational, and clinical research. Corefacilitiesandinfrastructurearefundedthroughmanymechanisms.ThedollaramountsforP30,R24,andU24awardscanbecaptured,buttheseawardsarenot100%infrastructure.ItisalsopossibletodeterminethenumberofP30,P50,andP01coresbutnotthedollarsassociatedwiththem.Moreover,anycoresassociatedwithR01,U-seriesmechanisms,etc.,arenotcapturedatanylevel.Forthereasonsdiscussedearlier,italsoproveddifficulttoclassifycorefacilitiesandinfrastructureaseither“translational”or“nottranslational.”
4. A database needs to be created that completely and accurately tracks and codes the individual components and projects of multiproject mechanisms (e.g., P01, EDRN, SPORE, and P30 awards).
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 117
Report of the NCAB Translational Research Working Group—Appendix D
Award Category Awards Coded as Translational
Total Active Awards*
% of Active Awards Coded as
Translational
Estimated Funds in FY04 for
Translational Awards ($M)
Program and Cooperative Awards
P01 107 207 51.7 215.0P20 8 34 23.5 3.0SPORE (P50) 58 58 100.0 131.7ICMIC (P50) 7 7 100.0 15.8EDRN (U01/U24) 28 28 100.0 21.8MMHCC (U01) 10 23 43.5 8.1Other U01 122 209 58.4 98.6U19 5 18 27.8 3.7NTROI (U54) 3 3 100.0 3.8Other U54 10 19 52.6 13.0U56 4 40 10.0 1.6DDG projects 18 18 100.0 11.1RAID projects 45 45 100.0 16.3RAPID projects 19 19 100.0 3.1
Career Development
K01 14 116 12.1 1.9K05 1 19 5.3 0.1K07 37 93 39.8 4.8K08 21 139 15.1 2.5K12 21 21 100.0 8.8K22 13 42 31.0 1.4K23 55 64 85.9 6.8K24 25 34 73.5 2.2
Individual Research
R01 1,161 4,450 26.1 447.0R03 150 320 46.9 8.1R21 288 599 48.1 43.8R33 62 121 51.2 24.2R37 11 74 14.9 6.6
Small Business
R41 (STTR Phase 1) 28 42 66.7 4.7R42 (STTR Phase 2) 12 19 63.2 3.8R43 (SBIR Phase 1) 87 246 35.4 13.3R44 (SBIR Phase 2) 102 176 58.0 39.4
Intramural
Z01 257 630 40.8 164.4
Total 2,789 7,933 35.2 1,330.4
Table 1. Awards Identified as Translational by Project Funding Mechanisms
* Totalawardsidentifiedasbeingactiveinfiscalyear2004fromtheCancerResearchPortfolio(intramuralawardsandinitiativeprogramslikeICMIC),theDevelopmentalTherapeuticsProgram(DDGandRAID),theDivisionofCancerPrevention(RAPID),andtheResearchAnalysisandEvaluationBranch(allothermechanisms).
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Table 2. Awards Identified as Translational by Infrastructure Funding Mechanisms
Award Category Awards Coded as Translational
Total Active Awards*
% of Active Awards Coded as
Translational
Estimated Funds in FY04 for
Translational Awards ($M)
Infrastructure*
P30 Cancer Centers 54 61 88.5 212.5R24 8 43 18.6 1.5U24 (excluding EDRN) 8 14 57.1 6.0Total 70 118 61.0 220.0
Extramural Core Facilities
Core Facilities supported through SPORE, P30, and P01 awards† 1,165 1,364 85.4 N/A
* Itshouldberecognizedthatsomeindividualawardsof“projectfunding”mechanismsareinfactusedtofundinfrastructure(e.g.,14Z01andtwoU54awardswereidentifiedthatweresolelyforinfrastructuralpurposes)andsomeCancerCenterfundsareusedtosupportprojects.
† TheExtramuralCoreFacilitiessectionshowsnumbersforthecorefacilitiesidentifiedatSPOREs,comprehensiveandclinicalP30s,andtransla-tionalP01s(AwardsCodedasTranslational)andatallSPOREs;basic,comprehensive,andclinicalP30s;andtranslationalandnontranslationalP01s(TotalAwardsReviewed).ThenumberofcorefacilitiesisnotdirectlyrelatedtotheestimatedFY2004fundingoftheInfrastructureawardcategory,whichdoesnotincludefundsforSPOREsandP01s.
Appendix Figures: Cross-Tabulations of NCI Translational Research Portfolio
Figure 1A. Percentage of the total 2,789 project funding awards identified as translational in FY 2004 supported by each NCI Division, Center, and Office.
* OfficeoftheDeputyDirectorforExtramuralScience(DDES)includestheOfficeofCenters,TrainingandResources(CancerCentersandSPOREs),theOfficeofCancerComplementaryandAlternativeMedicine,andtheOfficeofGrantProgramCoordination.
DDES* 9%
CCR 8%
DCB 11%
DCCPS 22%
DCTD 39%
DCP 9% DCEG
2%
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Figure 1B. Percentage of the total $1.33 billion in funding identified as translational in FY 2004 supported by each NCI Division, Center, and Office.
Figure 1C. Percentage of total FY 2004 funding in each NCI Division, Center, and Office identified as translational.*
* MostawardswithNIHCAcodesof0%wereexcludedfromthereview;however,thepercentagesshowninthefigurearebasedonthetotalnumberofactiveawardsinFY2004foreachDivision,Center,orOffice.Therefore,thepercentagesrepresentminimalpercentagevalues.TheextentthatprojectswithNIHCAquartileof0%aretranslationalwasbeyondthescopeofthisanalysis.
DDES 13%
CCR 7%
DCB 8%
DCCPS 19%
DCTD 39%
DCP 9%
DCEG 5%
DDES DCB DCEGCCR DCCPS DCP DCTD
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Figure 2A. Percentage of the 2,705 awards identified as translational in FY 2004 that are funded through the major funding mechanisms.*
* Thenumberofawardsisdifferentfromthetotalnumberofawardsidentifiedastranslational(2,�89)duetoexclusionof82RAID,RAPID,andDDGprojectsactiveinFY2004thatwereprimarilyfundedthroughcontractsandnotthroughthemajorfundingmechanismcategoriesandtwoEDRNU24infrastructure-basedawardsthatalsodidnotmatchthemajorfundingmechanismcategories.
Individual Research Awards (R01, R03, R21, R33, and R37)
62%
Intramural Awards 10%
Career Development Awards (K-series)
7%
Program and Cooperative Awards (P01, P50, U01,
and other U-series) 13%
Small Business Awards (R41–R44)
8%
Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41–R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIntramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.
Figure 2B. Percentage of the $1.30 billion in funding identified as translational in FY 2004 supported through the major funding mechanisms.
Individual Research Awards (R01, R03, R21, R33, and R37)
40%
Intramural Awards 13%
Program and Cooperative Awards (P01, P50, U01,
and other U-series) 40%
Career Development Awards (K-series)
2%
Small Business Awards (R41–R44) 5%
Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41–R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIntramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.
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Figure 2C. Percentage of total FY 2004 funding within each award mechanism that was identified as translational.*
* AmajorityofindividualresearchawardswerenotreviewedbecausetheyhadtheNIHCAquartileof0%,whileamajorityofawardsintheothermechanismcategorieswerereviewed.Thepercentagesinthisfiguremaybeconsideredminimalpercentages,asinFigure2A(seefootnote6onpage25).
Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41-R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIn-tramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.
Career Development
Awards (K-series)
Individual Research Awards (R01, R03, R21, R33, and R37)
Intramural Awards
Program and Cooperative
Awards (P01, P50, U01, and other U-series)
Small Business Awards
(R41–R44)
Figure 3A. Percentage of the 2,707 project funding awards identified as translational in FY 2004 made to major categories of institution.*
Non-Cancer Center Institute 35%
NCI-Designated Cancer Center
56%
Intramural Research 9%
Included:Researchawardstoinstitutionsdesignatedascomprehensiveorclinicalcancercenters,researchawardstoinstitutionsnotdesig-natedascomprehensiveorclinicalNCIcancercenters,andNCIintramuralawards.Notincluded:RAID,RAPID,andDDGawards..
* Thenumberofawardsisdifferentfromthetotalnumberofawardsidentifiedastranslational(2,�89)duetoexclusionofthe82RAID,RAPID,andDDGprojects.
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Figure 3B. Percentage of the $1.30 billion in funding identified as translational in FY2004 awarded to major categories of institution.
Non-Cancer Center Institute 31%
NCI-Designated Cancer Center
56%
Intramural Research 13%
Included:Researchawardstoinstitutionsdesignatedascomprehensiveorclinicalcancercenters,researchawardstoinstitutionsnotdesig-natedascomprehensiveorclinicalNCIcancercenters,andNCIintramuralawards.Notincluded:RAID,RAPID,andDDGawards..
Figure 3C. Percentage of total FY 2004 funding at major categories of institutions that was identified as translational.
NCI-Designated Cancer Center
Non-Cancer Center Institution
Intramural Research
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Figure 4. Percentage of the total 2,789 project funding awards identified as translational in FY2004 cross-tabulated by the seven major CSO categories.*
* AwardsassignedtotwoormoreCSOcategoriesarecountedtowardallassignedcategories.
Prevention 13%
Early Detection, Diagnosis, and Prognosis
19%
Biology 8%
Model Systems
1%
Etiology 20%
Treatment 34%
Figure 5A. NIHCA quartile of the 2,296 project funding awards active in FY 2004 that had a 25%-100% NIHCA code and were identified as translational.*
Included:AllactiveextramuralawardswithNIHCAquartileassignmentsof25%-100%identifiedastranslational.Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects,andawardswith0%NIHCAquartile.
* ProjectswithNIHCAquartileof0%werenotincludedbecauseonly8%oftheseawardswerereviewedtoidentifytranslationalresearchprojectsandthesetofprojectsreviewedisnotarepresentativesamplingofthe0%NIHCAawards.Examiningallsuchprojectswasbeyondthescopeoftheportfolioanalysis.
NIHCA = 100 56%
NIHCA = 25 22%
NIHCA = 50 19%
NIHCA = 75 3%
Cancer Control, Outcomes, and
Survivorship 5%
124 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
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Figure 5B. Percentage of awards in each NIHCA quartile identified as translational.*
* CertainclinicalresearchU-seriesprograms(e.g.,PhaseIU01trialists,AmericanCollegeofRadiologyImagingNetwork[ACRIN],thecooperativegroups,andCommunityClinicalOncologyPrograms[CCOPs])arenotintendedtobecoveredbythisinitiative.
Included:AllactiveextramuralawardswithNIHCAquartileassignmentsof25%-100%identifiedastranslational.Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects,andawardswith0%NIHCAquartile.
NIHCA = 100NIHCA = 25 NIHCA = 50 NIHCA = 75
Figure 5C. Percentage of all active FY 2004 extramural project funding awards by NIHCA quartile.
NIHCA = 50 9%
NIHCA = 25 14%
NIHCA = 100 25%
NIHCA = 75 1%
NIHCA = 0 51%
Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects.
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Appendix E: Process Analysis for the NCI Translational Research Working Group
Introduction and Summary
Inordertoinformitsdeliberations,theNationalCancerInstitute(NCI)TranslationalResearchWorkingGroup(TRWG)initiallydevelopedfivedevelopmentalpathwaystoclinicalgoalsencompassingriskassessmentdevices,agents,immuneresponsemodifiers,interventivedevices,andlifestyleinterventions.AttheDecember2005planningmeeting,TRWGmembersdecidedtoexamineseveralcasestudiesoftranslational“successes”alongeachofthesedevelopmentalpathways.Thegoalwastogaininsightsintothefollowingquestions.
• Whatpathsdosuccessestake?Aretherecommonalitieswithin/acrossthecasesexamined,oriseachtranslationunique?
• Evenforsuccesses,aretherebottleneckswherediscoveriesareheldup?Ifso,where?
• Whatrolesdoacademia,industry,andNCIplayinsuccessfultranslation?
• Whatinsightsdothecasestudiessuggestregardingthedevelopmentalpathwaystoclinicalgoals?
Twentycasestudiesspanningthefivedevelopmentalpathwaystoclinicalgoalswerecompleted.ThisdocumentpresentsthemethodsusedforidentifyingtheNCI-sponsoredtranslationalsuccesses,thekeyfindingsfromtheanalysis,andrepresentativesummariesofthecasesexamined.
Methodology
Identification of Case Study Candidates
AftertheDecember2005planningmeeting,membersoftheTRWGnominatedcandidatecasestudiesrepresentingeachofthedevelopmentalpathways.TheTRWGco-chairsselectedcasestudiesfromamongthenominees,aimingforadiversesetofcaseswithineachdevelopmentalpathway.
Data Collection
DatacollectionoccurredduringJanuaryandFebruary2006.Datacollectionincludedidentificationandreviewofpeer-reviewedpublications,tradeliterature,patentfilings,clinicaltrialabstracts,andfundingdata(includingNationalInstitutesofHealth(NIH)andnon-NIHfundingwhereavailable)foreachofthetranslationalresearchsuccesses.Keyparticipantswereidentifiedforeachtranslationalresearchsuccessandinterviewedwherepossible.TwentycaseswerecompletedinadvanceoftheTRWGRoundtableinFebruary2006.
• Risk Assessment Devices
BladderCancerEarlyDetection:MicrosatelliteInstabilityAssayofUrinarySediment
BladderCancerEarlyDetection:FluorescenceIn-SituHybridizationAssayofUrine
ProstateCancerEarlyDetection:ProteinExpressioninSerum
FDG-PETforEarlyDetection
•
•
•
•
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• Agents
Avastin
DNAMethyltransferaseInhibitor(e.g.,Vidaza)/HistoneDeacetylaseInhibitorCombinations
Bortezomib/Velcade
Anti-HER2/neuLiposomes
Celecoxib
TNFerade
• ImmuneResponseModifiers
HER2/neuBreastCancerVaccine
RNA-TransfectedDendriticCells
CombinationofMDX-010/anti-CTLA-4AntibodywithMelanoma(andProstateCancer)Vaccines
Cell-BasedVaccinesforPancreaticCancer
GloboHBreastCancerVaccines
• Interventive Devices
RadiofrequencyAblation
Three-DimensionalConformalRadiationTherapyforProstateCancer
FDG-PETDeviceDevelopment
• Lifestyle Alterations
Exercise,Diet,andBreastCancer
SmokingCessationandLungCancer
Key Findings
Becauseonlyasmallsamplesizewasconsidered,norobustgeneralconclusionscanbedrawnfromthecasestudies.Nevertheless,severalinterestingpatternsemerged.
1. ThecasesdrewuponawidevarietyofNCIandNIHfundingmechanisms.Casesincludedtranslationalactivitiesfundedthroughasinglelarge-scale,team-basedprogram(e.g.,SpecializedProgramsofResearchExcellence(SPORE),EarlyDetectionResearchNetwork(EDRN)),othersfundedthroughaseriesofindividual-investigatorawards(e.g.,R01,K-series,SmallBusinessInnovationResearchProgram(SBIR)/SmallBusinessTechnologyTransferProgram(STTR)),andstillothersthroughtheNCIintramuralresearchprogram.Severalcasesusedacombinationofindividual-investigatorawardsandteam-basedprojects,whilesomewerefundedthroughotherNIHInstitutes(e.g.,NationalInstituteofGeneralMedicalScience(NIGMS),NationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK),NationalInstituteofAllergyandInfectiousDiseases(NIAID))aswellasNCI.Inthecasesinvestigated,itwasfoundthatbothNCIandindustrycouldbeinvolvedatanystagealongthetranslationcontinuumfromearly-tolate-stage.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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2. Themajorityofthecasesencounteredbottlenecksorchallengesinachievingsuccess.Severalcasesrequiredthedevelopmentofnewassaysorscreeningtechniquestovalidatethediscovery;severalencounteredbottlenecksinpreclinicaldevelopment(e.g.,GMPmanufacturing);andothersencountereddifficultiesinearly-stageclinicaltrialsbecauseofFoodandDrugAdministration(FDA)approvalorpatientrecruitmentissues.
3. Arangeofinteractionsamongstakeholderswasobserved.Casesincluded“traditional”handoffsfromacademiatoindustry,translationthatoccurredprimarilyinacademiabutwithindustryfundingofspecificprocesssteps,fullpublic-privatepartnerships,andevenexampleswherefundamentaldiscoveriesmadebyprivateindustrybenefitedfromNCI-fundedtranslationalresources.
4. Thecasestudiessuggestedcertaininsightsintothedevelopmentalpathways.
Somecasesbydefinitionspannedmultiplepathways.FDG-PET,forexample,functionsasariskassessmentdevice,butitwasdevelopedasacombinationofimagingagent(FDG)andaninterventivedevice(PET).Inotherexamples,activityinonepathwayledtodiscoveriesrelevanttootherpathways(e.g.,celecoxibdevelopmentledtothediscoveryofanewcandidatebiomarkerofbiologicalresponse).
TheTRWGdevelopmentalpathwaysareidealizedrepresentationsofthetranslationalresearchprocess.Forexample,severalcasesintheinterventivedevicepathwayskippedstepsorevenwholesegmentsofthepathwayandseveralimmuneresponsemodifiercasesinvolvedmultipleiterationsofrefinementbeforereachingclinicaltrials.
Conclusions and Future Considerations for Translational Research Analysis
Theprocessanalysisexerciseshowedthatinnoneofthecasesexaminedwastheentiredevelopmentalpathwayfundedbyasingle,comprehensiveprogramormechanismorbyasystematicallycoordinatedseriesofprogramsormechanisms.Individualinvestigatorsorteamsassembledfundingforeachcase,withtheparticularcombinationsthatadvancedaconceptthroughthedevelopmentalpathwayoftendependingontheingenuityoftheinvestigators.
Thecasessuggestthattranslationalresearchwouldbefacilitatedbytheavailabilityofmoreunifiedandbetter-coordinatedfundingmechanisms.Theyalsodemonstratetheabsenceofcriticalsystem-leveltranslationalresearchmetrics(e.g.,thefractionofsuccessesthatareadvancedthroughspecificprogramsormechanismsorthefractionthatencounterbottlenecksatspecificpointsineachdevelopmentalpathway).Creationofdatasystemsthatcanprovidesuchinformationinalogisticallystraightforwardandpreciselydefinedwaywillbebeneficialforimprovingthemanagementoftranslationalresearch.
Case Study Summaries
Summariesof10representativecasestudies,tworepresentingeachofthefiveinitialdevelopmentalpathways,arepresentedbelow.Casestudiesarenotincludedforthesixthpathway,image-basedriskassessmentagents/techniques,becausethispathwayhadnotbeendevelopedatthetimetheprocessanalysiswasconducted.Thecasestudiessummarizedarelistedbelow.
• Risk Assessment Devices
BladderCancerEarlyDetection:MicrosatelliteInstabilityAssayofUrinarySediment
BladderCancerEarlyDetection:FluorescenceIn-SituHybridizationAssayofUrine
• Agents
Bortezomib/Velcade
Celecoxib
•
•
•
•
•
•
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• ImmuneResponseModifiers
HER2/neuBreastCancerVaccine
Cell-BasedVaccineforPancreaticCancer
• Interventive Devices
RadiofrequencyAblation
Three-DimensionalConformalRadiationTherapyforProstateCancer
• Lifestyle Alterations
Exercise,Diet,andBreastCancer
SmokingCessationandLungCancer
•
•
•
•
•
•
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Bladder Cancer Early Detection: Microsatellite Instability Assay of Urinary Sediment
Summary:Intheearlytomid-1990s,severalresearchgroupsreportedstudiesindicatingthatmicrosatelliteinstabilitycouldhavepotentialutilityasamarkerforearlydetectionofcancer.In1996,theSidranskyandSchoenberggroupsatJohnsHopkinsUniversityreportedthaturinemicrosatelliteinstabilityassaysdetectedbladdercancerinpatientswith95%sensitivitywhereasurinecytologyhadonly50%sensitivity.Asecondstudyreportedin1997demonstratedthattheurinemicrosatelliteassaycouldalsodetectbladdercancerrecurrencewithapproximately90%sensitivity.BothofthesestudieswerefundedbyOncorInc.andledtofilingofpatentapplicationsin199�whichthenledtotheissuanceoffourU.S.patents.
Thetechnologyandintellectualpropertywerelicensedin2000toCangenBiotechnologies,whodevelopedaninitialtestkit.TheCangentestkitwasvalidatedbytheEDRNbiomarkerreferencelaboratoriesusingretrospectivesamplesetscollectedatJohnsHopkins.In2004EDRNinitiatedamultisiteprospectiveBiomarkersPhaseIIIstudy(whichdiffersfromaPhaseIIIclinicaltrial)with300patientsand200controlstocomparemicrosatelliteanalysiswithcystoscopyandcytologyfordetectionofbladdercancerrecurrence.ThestudywasclosedtoaccrualinJanuary2007with270patients.TheresultsofthistrialwillbeusedbyCangentopursueFDAlicensureofitstestkit.
Relationship to TRWG Pathway
Developmentofthemicrosatelliteassaycloselyfollowedtheriskassessmentdevicepathway.
Bottlenecks
1. BankruptcybyOncor,theinitiallicenseeofthetechnology,ledtoa2-yeardelayindevelopmentwhiletheintellectualpropertyrightsweretiedupinlegalproceedings.RecoveryoftherightsrequiredthecombinedeffortofJohnsHopkinsandCangen,whichbecameinterestedinthetechnologybecauseaco-discovererwastheirChiefScientificOfficer.
2. Developmentofapractical,validatedtestkitrequiredmigrationfromtheradioactivity-basedassaydevelopedatJohnsHopkins,whichrequiredsubjectivereadingandinterpretationbyatrainedobserver,toafluorescence-basedassaywhichusedautomatedsequencing,reading,andinterpretation.Industryinvolvementwascriticaltodevelopandvalidatethisautomatedassay.
3. AccrualtotheBiomarkersPhaseIIItrialwasinitiallyasignificantbottleneck,butthiswasovercomebytheadditionofmoreclinicalcenters.
Key Observations
1. Tomovenew,broad-basedrisk-assessmenttechnologiesforward,itisimportanttoidentifyaninitialdiseasetargetwithastrongclinicalneedinordertoattractindustryattention.
2. Intellectualpropertylicensingisessentialbutsuchlicensingmayinadvertentlyencumberthetechnologyandimpedeitsdevelopment.
3. Developmentofpractical,validatedassaymethodologiescanbechallengingforacademiclabs.
4. Thestandardmodelofindustryfundingoflate-stageratherthanearly-stagedevelopmentisnotalwaysfollowedastheearlytranslationalworkwasfundedlargelybyindustrywhilethedefinitiveBiomarkersPhaseIIItrialwasfundedbyNCI.
5. SmalldevicecompaniesoftenrelyonNCItofundthelargeclinicalstudiesnecessarytosupportFDAapprovalofnewcancerclinicaltests.
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Sources
• InterviewwithDr.DavidSidransky/Dr.SudhirSrivastava(January31,2006)
Literature
• MaoL,LeeDJ,TockmanMS,ErozanYS,AskinF,SidranskyD.Microsatellitealterationsasclonalmarkersforthedetectionofhumancancer.ProcNatlAcadSci.1994;91(21):9871-5.
• MaoL,SchoenbergMP,ScicchitanoM,ErozanYS,MerloA,SchwabD,SidranskyD.Moleculardetectionofprimarybladdercancerbymicrosatelliteanalysis.Science.1996;271(5249):659-62.
• SteinerG,SchoenbergMP,LinnJF,MaoL,SidranskyD.Detectionofbladdercancerrecurrencebymicrosatelliteanalysisofurine.NatMed.1997;3(6):621-4.
• PepeMS,EtzioniR,FengZ,PotterJD,ThompsonML,ThornquistM,WingetM,YasuiY.Phasesofbiomarkerdevelopmentforearlydetectionofcancer.JNCI.2001;93(14):1054-61.
Patent Search
• Sidransky.Nucleicacidmutationdetectionbyanalysisofsputum(#5,561,041).FiledNovember12,1993;receivedOctober1,1996.
• Sidransky.Detectionofhypermutablenucleicacidsequenceintissue(#5,935,�8�).FiledMay12,199�;receivedAugust10,1999.
• Sidransky.Methodfordetectingcellproliferativedisorders(#6,291,163).FiledAugust28,1997;receivedSeptember18,2001.
• Sidransky.Methodfordetectingcellproliferativedisorders(#6,780,592).FiledSeptember10,2001;receivedAugust24,2004.
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Bladder Cancer Early Detection: Fluorescence In-Situ Hybridization Assay of Urine
Summary:Fluorescencein-situhybridization(FISH)wasoriginallydevelopedbytheGraygroupatLawrenceLivermoreNationalLaboratoryinthelate1980susingDepartmentofEnergy(DOE),NCI,andNationalInstituteofChildHealthandHumanDevelopment(NICHD)funding.Intheearlytomid-1990s,severalacademicresearchersbegantoworkonapplicationofFISHtechnologyforearlydetectionofbladdercancer.Atthesametime,VysisInc.wasfurtherdevelopingtheFISHtechnologyforuseinclinicaltestsanddemonstratedtoFDAthatassaysbasedonFISHweresufficientlyrobustandreproducibletobeusedforclinicalpurposes.
In1998,VysisidentifiedtheuseofFISHforearlydetectionofbladdercancerasacommercialtargetbaseduponthecombinationofclinicalneed(existingtestshadlimitedsensitivity/specificity)andtheassessmentthatVysis’sFISHtechnologycouldimproveuponthosetests.ThecompanycollaboratedwiththeUniversityofBaselandMayoClinictoobtainsamplesandclinicaldatasetsforvalidatingthetechnology(1999-2000)andtopursuelarge-scaleprospectivestudies(2000-2001).FDAapprovalfortheUroVysiontestwasgrantedinAugust2001.
Relationship to TRWG Pathway
DevelopmentoftheFISHassayfollowedtheriskassessmentdevicepathwayquiteclosely.
Bottlenecks
Nosignificantbottleneckswerereported.
Key Observations
1. TheTRWGpathwayeffectivelydescribesthestepsusedtotranslatetheFISHtechnologyintoapracticaltestforbladdercancer.AllthreedecisionpointsforentryintotranslationaldevelopmentwereaddressedinVysis’sassessment;namely,thatthetechnologywasmatureandthatbladdercancerwasanappropriateapplicationtopursue.
2. Successfultranslationinvolvedindustryperformingtwocriticalroles.ThefirstwasrefinementandvalidationoftheFISHtechnologydevelopedwithgovernmentfundingintoamethodologysufficientlyrobustandreliabletoserveasthebasisforclinicaltests.ThesecondinvolvedbuildingonreportsbyseveralacademicinvestigatorsofthepotentialutilityofFISHforthedetectionofbladdercancerinordertodevelopanFDA-approvedtest.
3. Collaborationwithacademicinvestigatorswasimportantinorderforindustrytoobtaintheclinicalspecimensnecessarytodevelopandvalidatethenewcancerclinicaltest.
Sources
• InterviewwithDr.SteveSeelig,Abbot(February7,2006)
• AdvancedTechnologyProgramfactsheet,“BarCodeDiagnosticsforDNAAnalysis”
Literature
• vanDekkenH,PinkelD,MullikinJ,GrayJW.Enzymaticproductionofsingle-strandedDNAasatargetforfluorescenceinsituhybridization.Chromosoma.1988;9�(1):1-5.
• SokolovaIA,HallingKC,JenkinsRB,BurkhardtHM,MeyerRG,SeeligSA,KingW.Thedevelopmentofamultitarget,multicolorfluorescenceinsituhybridizationassayforthedetectionofurothelialcarcinomainurine.JMolDiagn.2000;2(3):116-23.
132 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
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• HallingKC.VysisUroVysionforthedetectionofurothelialcarcinoma.ExpertRevMolDiagn.2003;3(4):507-19.Erratumin:ExpertRevMolDiagn.2004;4(2):266.
Patent Search
• Hallingetal.Methodandprobesetfordetectingcancer(#6,174,681).FiledMarch5,1999;receivedJanuary16,2001.
• Hallingetal.Methodandprobesetfordetectingcancer(#6,376,188).FiledJuly21,2000;receivedApril23,2002.
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Bortezomib/Velcade
Summary
Interestintheroleoftheproteasome(acomplexofenzymesinvolvedindegradationofmisfoldedproteins)incarcinogenesisgrewduringthemid-1990s.In1994researchersatProScriptInc.developedagroupofproteasomeinhibitorsthatappearedtobeeffectiveinpromotingapoptosisofcancercells.Aspartoftheirresearch,theProScriptgroupalsodevelopedanin vitroassayforproteasomeinhibition,whichservedasasurrogatemarkerfortheeffectivenessofthisclassofdrugs.Beginningin1995,theNCIDevelopmentalTherapeuticsProgram(DTP)assistedProscriptwithin vitroandanimalmodelstudiesthatidentifiedoneoftheseinhibitors(PS-341,latertrade-namedVelcade)asalikelycandidateagentfromamongthegroupofcompoundsProScriptprovidedfortesting.ProscriptperformedpreclinicaldevelopmentofPS-341internallyandDTPassistedwithformulationstudies.
PhaseIclinicaltrialsinprostatecancerwereperformedbyacademicinvestigatorsbeginninginOctober1998withCaPCure(ProstateCancerFoundation)funding.In1999,preclinicalstudiesandPhaseItrialsinmultiplemyelomawereperformedatDana-FarberCancerInstitute,fundedbyNCI.TheacquisitionofProScriptbyMillenniumPharmaceuticalsin1999providedadditionalresourcesfordevelopmentofthedrugandMillenniumconductedPhaseIIBtrialsinmultiplemyelomapatientsduring2001-2002.Theresultswerepresentedinlate2002andledtoFDAapprovalofthedrugin2003.Throughoutdevelopment,theFDAwasquitesupportiveofbringingthisnewclassofcompoundsintoclinicaltrials.
Relationship to TRWG Pathway
DevelopmentofVelcadelargelyfollowedtheTRWGagentdevelopmentpathway.Atthebottomofthepathway,thedrug’sdevelopmentbranchedintomultiplePhaseItrialsforprostatecancer,multiplemyeloma,andseveralotherdiseasesites.
Bottlenecks
SeveralbottlenecksinthedevelopmentofVelcadewereidentified.Thesebottlenecksincluded(a)developinganassayforproteasomeinhibitionthatallowedidentificationofasafeandeffectivedosagerange(overcomebyProScriptscientists),(b)formulationofthedrug(overcomebyDTP),and(c)interestingacademictrialistsinbringingthedrugintoearly-stageclinicaltrials(overcomethroughentrepreneurshipbyProScriptscientists).
Key Observations
1. DevelopmentofVelcadeinvolvedcollaborationamongindustry,NCI,academictrialists,andfoundations.ClosecoordinationamongthestakeholdersnotonlyfacilitatedvalidationofthediscoveryandpreclinicaldevelopmentofthedrugbutalsospedtheenrollmentofmultiplemyelomapatientsintothePhaseIItrialsthatprovidedthedatatosupportFDAapproval.
2. Small-to-midsizecompaniesoftendonothavesufficientin-housecapabilitytodevelopapromisingtherapeuticagent.Inthiscase,DTPprovidedassayandanimalmodelcapabilitiesthatassistedProScriptinidentifyingaleadagentcandidateaswellasformulationcapabilities.Thisdemonstratesthevalueofacademic-industry-NCIcollaborationintranslationalresearch.
3. Late-stagedevelopmentofthedrugwasfacilitatedbyinvolvementofalargepharmaceuticalcompany.WithouttheacquisitionofProScriptbyMillenniumPharmaceuticals,developmentmayhaveceasedbecauseProScriptdidnothavethefinancialresourcestocontinuewithlate-stageclinicaltrials.
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Sources
• “MyelomaToday”(InternationalMyelomaFoundation)profileofDr.JulianAdams,June2003
• NationalCancerInstitute/DevelopmentalTherapeuticsProgram,“SuccessStory:Velcade(NSC681239),”http://dtp.nci.nih.gov/timeline/noflash/success_stories/S6_Velcade.htm
• NationalCancerInstitute/DevelopmentalTherapeuticsProgram,“Velcade(PS-341),”http://dtp.nci.nih.gov/timeline/posters/Velcade.pdf
• InterviewwithDr.ChristopherLogothetis,MDAnderson(February10,2006)
• InterviewwithDr.KennethAnderson,BethIsraelDeaconessMedicalCenter(February7,2006)
Literature
• AdamsJ,BehnkeM,ChenS,CruickshankAA,DickLR,GrenierL,KlunderJM,MaYT,PlamondonL,SteinRL.Potentandselectiveinhibitorsoftheproteasome:dipeptidylboronicacids.BioorgMedChemLett.1998;8(4):333-8.
• AdamsJ,PalombellaVJ,SausvilleEA,JohnsonJ,DestreeA,LazarusDD,MaasJ,PienCS,PrakashS,ElliottPJ.Proteasomeinhibitors:anovelclassofpotentandeffectiveantitumoragents.CancerRes.1999;59(11):2615-22.
• TeicherBA,AraG,HerbstR,PalombellaVJ,AdamsJ.Dana-FarberCancerInstituteandJointCenterforRadiationTherapy.ClinCancerRes.1999;5(9):2638-45.
• HideshimaT,RichardsonP,ChauhanD,PalombellaVJ,ElliottPJ,AdamsJ,AndersonKC.TheproteasomeinhibitorPS-341inhibitsgrowth,inducesapoptosis,andovercomesdrugresistanceinhumanmultiplemyelomacells.CancerRes.2001;61(7):3071-6.
• RichardsonP.Clinicalupdate:proteasomeinhibitorsinhematologicmalignancies.CancerTreatRev.2003;29(Suppl1):33-9.
• TwomblyR.Firstproteasomeinhibitorapprovedformultiplemyeloma.JNCI.2003;95(12):845.
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Celecoxib
Summary
TheCOX-2inhibitorcelecoxibwasinitiallydevelopedasananti-inflammatoryagentbySearle(laterPharmaciaandthenPfizer).Epidemiologicdatapublishedduringthelate1980sshowingthataspirinusewasassociatedwithdeclinesincolorectalcancer(CRC)suggestedthataspirinorothernon-steroidalanti-inflammatorydrugs(NSAIDs)couldpotentiallybeusedasapreventativeortherapeuticagentincancer.Thishypothesiswasfurthersupportedbystudiesinanimalmodelsofcarcinogenesiswhichexaminedthepotentialroleofprostaglandinsincancerprogression.Intheearly1990s,thegenerationofprostaglandinsfromarachadonicacidwasdeterminedtoarisefromtwodistinctcyclooxygenase(COX)enzymes—COX-1,whichwasassociatedwithamorebasal,housekeepingrole,andaninducibleCOX-2,whichwasresponsivetoavarietyofstimuliassociatedwithinflammationandcancer.
Basedontheseobservations,theDuBoisgroupatVanderbilt,fundedbyR01grantsfromtheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesandseveralothersources,demonstratedseveralimportantfindings.First,overexpressionofCOX-2increasedtheinvasivenessandprostaglandinproductionofcoloncancercellsinculturewhichcouldbereversedbygeneticorpharmacologicCOX-2inhibition.Second,tissuestudiesshowedCOX-2wasexpressedinhumanadenocarcinomas.Third,mousemodelstudiesdemonstratedthatCOX-2inhibitorscouldreducetumorformationbycoloncancercelllinesconstitutivelyexpressingCOX-2,buthadnoeffectoncancercelllineslackingCOX-2.Theseobservationsweresupportedbystudiesfromseveralotherepidemiologylaboratorieswhichconfirmedthesedata,demonstratedtherelevanceofCOX-2toearlystagesofcolorectalcarcinogenesis,andsuggestedthatNSAIDsand/orCOX-2inhibitorswereassociatedwithreductionsincolorectaladenomaincidence,colorectalcancerincidence,andCRC-associatedmortality.AllofthesefindingssuggestedthatcelecoxibandotherCOX-2inhibitorscouldhavepromiseaseffectivechemopreventiveagentswithfewerGIsideeffects(e.g.,gastroduodenalulceration)andthuswereparticularlyappealingagentsforclinicaltrialsincolorectalneoplasiaprevention.
AspreclinicaldevelopmentoncelecoxibhadbeendonepreviouslybySearle,itwasthoughtatthetimethattherewasnoneedforadditionaltoxicology/pharmacologybeforeintroducingtheagentintocancerchemopreventionclinicaltrials.NCI-fundedphaseIIpreventiontrialsbeganin1998inpatientsatveryhighriskforcolorectalcancerduetofamilialadenomatouspolyposis(FAP).SuccessinthistrialledtotheinitiationofseveraltrialsinpatientsatmoremoderateriskforCRCduetoprioradenomas.MerckinitiatedatrialofitsCOX-2inhibitor—rofecoxib(Vioxx)—in1999,andtheNCIandPfizerpartneredtoinitiateathree-armtrialofcelecoxib(attwodoses)versusplacebo(theAPCtrial).Pfizeralsoinitiatedasecond,multinationaltrialofsimilardesignwithcelecoxibversusplaceboin2000(thePreSAPtrial).Afterrofecoxibwasobservedin2004tocausecardiovasculartoxicity,bothPfizerandNCImonitoredtheirlarge-scalechemopreventivetrialscloselyandin2005,celecoxibwasfoundtobeassociatedwithanelevatedriskforseriouscardiovasculareventsintheAPCtrialaswell.
Althoughcelecoxibdidnotprovesufficientlysafeforwidespreadchemopreventiveuseinmoderate-riskindividuals,investigationoftheCOX-2pathway’srelevancetocancerhasledtocertainothertranslationalopportunities.Forexample,subsequentresearchintotheCOX-2pathwayhasuncoveredadownstreampathwaystep(thefinalstepinprostaglandinPGE2synthesis)whosedisruptionmayhavethesametherapeuticbenefitwithoutthetoxicityofCOX-2inhibition.Inaddition,theDuBoisgrouphasusedNCIfundingtoexploretheuseofCOX-2levelsasabiomarkerfordiagnosisofcoloncancerandEDRNhasalsofundedstudiesconcerningCOX-2’spotentialasabiomarkerofrisk.
Relationship to TRWG Pathway
Thepre-existingleadagentcandidateenteredthedevelopmentalpathwaybasedonobservational/epidemiologystudies,preclinicaldata,andapprovaloftheagentforuseinadifferentdiseasearea.Thisexamplealsoshowslinkagesbetweenpathways.Workintheagentpathwayhassuggestedconceptsfordevelopmentthroughthebiospecimen-basedriskassessmentdevicepathway.
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Bottlenecks
Althoughtoxicologywasnotviewedasabottleneckatthetime,developingmethodsthatcanidentifytoxicityassociatedwithlong-termuseisanimportantpotentialbottleneckinbringingforwardchemopreventiveagentsforuseinlow-tomoderate-riskpopulations.
Key Observations
1. AcompounddevelopedbyindustryforadifferentdiseaseareawastranslatedforuseincancerthroughtheinvolvementofacademicresearchersfundedbyNCIandotherInstitutes.
2. ResearchfundedbyotherNIHInstitutescanleadtodiscoveriesrelevanttocancer.
3. TheremaybeimportantdifferencesbetweenagentdevelopmentfortreatmentandforpreventioneventhoughtheycanbedescribedusingthesameTRWGdevelopmentalpathway.Thecelecoxibexamplehighlightsthecriticalroleofbalancingrisksandbenefitsinprevention,andsuggeststheimportantrolethatnewapproachestopreclinicaltoxicologicassessmentsmayplayinassessingtherisksassociatedwithapreventivecompound.
4. ClosecollaborationbetweenindustryandNCIfacilitatedtheconductoflargechemopreventiontrials.
Sources
• InterviewwithDr.RaymondDuBois,VanderbiltUniversity(January26,2006)
• InterviewwithDr.ErnestHawk,NCI(February8,2006)
Literature
• ThunMJ,NamboodiriMM,HeathCWJr.Aspirinuseandreducedriskoffatalcoloncancer.NEnglJMed.1991;325(23):1593-6.
• RosenbergL,PalmerJR,ZauberAG,WarshauerME,StolleyPD,ShapiroS.Ahypothesis:nonsteroidalanti-inflammatorydrugsreducetheincidenceoflarge-bowelcancer.JNCI.1991;83(5):355-8.
• EberhartCE,CoffeyRJ,RadhikaA,GiardielloFM,FerrenbachS,DuBoisRN.Up-regulationofcyclooxygenase2geneexpressioninhumancolorectaladenomasandadenocarcinomas.Gastroenterology.1994;107(4):1183-8.
• ReddyBS,RaoCV,SeibertK.Evaluationofcyclooxygenase-2inhibitorforpotentialchemopreventivepropertiesincoloncarcinogenesis.CancerRes.1996;56(20):4566-9.
• SteinbachG,LynchPM,PhillipsRKS,WallaceMH,HawkE,GordonGB,WakabayashiN,SaundersB,ShenY,FujimuraT,SuL,LevinB,GodioL,PattersonS,Rodriguez-BigasMA,JesterSL,KingKL,SchumacherM,AbbruzzeseJ,DuBoisRN,HittelmanWN,ZimmermanS,ShermanJW,KelloffG.Theeffectofcelecoxib,acyclooxygenase-2inhibitor,infamilialadenomatouspolyposis.NewEngJMed.2000;342(26):1946-52.
• SolomonSD,McMurrayJJV,PfefferMA,WittesJ,FowlerR,FinnP,AndersonWF,ZauberA,HawkE,BertagnolliM,fortheAdenomaPreventionwithCelecoxib(APC)StudyInvestigators:Cardiovascularriskassociatedwithcelecoxibinaclinicaltrialforcolorectaladenomaprevention.NEnglJMed.2005;352:1071-80.
• BertagnolliMM,EagleCJ,ZauberAG,RedstonM,SolomonSD,KimK-M,TangJ,RosensteinRB,WittesJ,CorleD,HessTM,WolojGM,BoisserieF,AndersonWF,VinerJL,BagheriD,BurnJ,ChungDC,DewarT,FoleyTR,HoffmanN,MacraeF,PruittRE,SaltzmanJR,SalzbergB,SylwestrowiczT,GordonGB,HawkETfortheAPCStudyInvestigators.Celecoxibforthepreventionofsporadiccolorectaladenomas.NEnglJMed.2006;355:873-84.
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• SolomonSD,PfefferMA,McMurrayJJV,FowlerR,FinnP,LevinB,EagleC,HawkE,LechugaM,ZauberAG,BertagnolliMM,ArberN,WittesJfortheAPCandPreSAPTrialInvestigators.Effectofcelecoxiboncardiovasculareventsandbloodpressureintwotrialsforthepreventionofcolorectaladenomas.Circulation.2006;114:1028-35.
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HER-2/neu Breast Cancer Vaccine
Summary
PreviousworkshowedthatthetumorantigenHER-2/neuisoverexpressedincertaintypesofbreastcancerandthatsomebreastcancerpatientshadexistentimmuneresponsesagainsttheHER-2/neuproteinalthoughtheresponsesfellshortoftherapeuticlevels.ThesefindingssuggestedthepossibilitythatHER-2/neuvaccinescouldtargetHER-2/neupositivebreastcancer.TheCheevergroupattheUniversityofWashington(UW)showedin1996thatitwasfeasibletoelicitanimmuneresponseinmousemodelsusingportionsoftheHER-2/neuproteinasanimmunogen.ThisworkwasfundedthroughanNCIR01grantoriginallyfocusedontheevaluationofimmuneresponsesagainstmelanoma.Patentapplicationswerefiledin1995throughUWclaimingimmunereactivitytoHER-2/neuproteinasthebasisfordiagnosisandtreatmentofHER-2/neu-associatedmalignancies.UWscientistsco-foundedastart-upbiotechcompany,Corixa,whichlicensedthepatentandcommencedGMPmanufacturingofaseriesofHER-2/neupeptidevaccinesusinganNCISBIRgrantasonesourceoffunds.
TheinitialPhaseItrialin1998wasconductedunderaUWINDwithCorixafunding.ThisinitialtrialledtomultipleCorixa-fundedPhaseItrialsincollaborationwithUWtranslationalscientistsinordertorefinethevaccineconstructandoptimizetheimmuneresponse.OnekeyrefinementwasthetransitionfromusingsmallerportionsoftheHER-2/neuproteintousingthefullextracellulardomainfusedtomajorportionsoftheintracellulardomainoftheprotein.
Inordertocontinuedevelopmentofthevaccine,CorixapartneredwithGSK.GSKwasessentialforfinancingtheprojectandformanufacturingthevaccineunderconditionsthatmaintainedthenaturalfoldingoftheextracellulardomain.ThevaccinewasalsoformulatedwithuniquecombinationsofadjuvantsavailabletoGSKandnotavailabletoacademicinvestigators.PhaseI/IItestingofthisimprovedvaccineformulationwasinitiatedin2004byGSKandCorixaincollaborationwithmultipleacademictranslationalresearchersincludingthoseatUW.ThevaccineformulationwasabletoinducesubstantialantibodyandTcellimmuneresponsesinbreastcancerpatientsandcontinuesindevelopmentatGSK.WhileCorixaandGSKmovedforwardwithimprovingtheHER-2/neuprotein-basedvaccine,otherUWscientists(fundedthroughNCIR01andK08grants)havebeensuccessfullyworkingonDNA-basedHER-2/neuvaccineapproaches.
Relationship to TRWG Pathway
Developmentfollowedtheimmuneresponsemodifierpathwaythroughmultipleiterationsofvaccineconstructionandadjuvantformulation,deliveryschemes,andvaccineregimens,bothinanimalmodelsandearly-phasehumanclinicaltrials.ThemultipleiterationsledtorefinementsoftheHER-2/neuvaccineconstructtofinallyachieveanimmuneresponsethatwasdeemedadequatetojustifytestingofthevaccineinlarger-scaletrials.
Bottlenecks
Preclinicaldevelopment/manufacturingrequiredbiotechandlarge-companyfinancialandtechnologicalresources.Thefinalvaccineformulationusedaseriesofadjuvantsnotcommonlyavailabletomostacademicresearchersorbiotechcompanies.
Key Observations
1. Successfulhandoffoftechnologyfromacademiatoindustrywasfacilitatedbyastrongintellectualpropertyposition,whichledtotheco-foundingofasmallbiotechcompanybytheacademicinventors.
2. Testingofthevaccineinpatientsrequiredthattheconstructedvaccinebe“handedback”toacademicinvestigators.
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3. Partnershipbetweenasmallbiotechcompanyandalargepharmaceuticalcompanywasnecessarytoovercomefinancial,manufacturingandadjuvantavailabilityhurdles.
4. PhaseItrialsofinitialvaccineconstructscanserveas“validationsteps”thatassistresearchersinrefiningapproachesanddevelopingimprovedvaccinesforsubsequentexpandedtrials.
Sources
• InterviewwithDr.MacCheever,FredHutchinsonCancerResearchCenter/UniversityofWashington(February6,2006)
Literature
• DisisML,GralowJR,BernhardH,HandSL,RubinWD,CheeverMA.Peptide-based,butnotwholeprotein,vaccineselicitimmunitytoHER-2/neu,oncogenicself-protein.JImmunol.1996;156(9):3151-8.
• DisisML,PupaSM,GralowJR,DittadiR,MenardS,CheeverMA.High-titerHER-2/neuprotein-specificantibodycanbedetectedinpatientswithearly-stagebreastcancer.JClinOncol.1997;15(11):3363-7.
• DisisML,GrabsteinKH,SleathPR,CheeverMA.GenerationofimmunitytotheHER-2/neuoncogenicproteininpatientswithbreastandovariancancerusingapeptide-basedvaccine.ClinCancerRes.1999;5(6):1289-97.
• DisisML,GooleyTA,RinnK,DavisD,PiepkornM,CheeverMA,KnutsonKL,SchiffmanK.GenerationofT-cellimmunitytotheHER-2/neuproteinafteractiveimmunizationwithHER-2/neupeptide-basedvaccines.JClinOncol.2002;20(11):2624-32.
• DisisML,SchiffmanK,GuthrieK,SalazarLG,KnutsonKL,GoodellV,delaRosaC,CheeverMA.EffectofdoseonimmuneresponseinpatientsvaccinatedwithanHER-2/neuintracellulardomainprotein-basedvaccine.JClinOncol.2004;22(10):1916-25.
• LimentaniS,DorvalT,WhiteS,CuriglianoG,CamponeM,DisisM,PiccartM,CheeverM,GérardC,BrichardV.PhaseIdose-escalationtrialofarecombinantHER2vaccineinpatientswithStageII/IIIHER2+breastcancer.JClinOncol.2005;23(165)PartIofII(June1Supplement):2520.
Patent Search
• Cheeveretal.ImmunereactivitytoHER-2/neuproteinfordiagnosisandtreatmentofmalignanciesinwhichtheHER-2/neuoncogeneisassociated(#5,876,712).FiledJune6,1995;receivedMarch2,1999.
• Cheeveretal.ImmunereactivitytoHER-2/neuproteinfordiagnosisandtreatmentofmalignanciesinwhichtheHER-2/neuoncogeneisassociated(#5,846,538).FiledJune�,1995;receivedDecember8,1998.Subsequentpatentsinclude#6,075,122—UniversityofWashingtonand#6,379,951—Corixa.
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Cell-Based Vaccine for Pancreatic Cancer
Summary
Inthelate1980sandearly1990s,anumberofstudieswerereportedindicatingthatmurinetumorcellstransducedtoexpressawiderangeofcytokinescouldinduceanimmuneresponseagainstthetransducedcellsandincertaincasesagainstsubsequentchallengewithnontransducedcellsorapre-existingtumor.In1993agroupincludingresearchersfromJohnsHopkinsUniversityreportedthatcellstransducedwithgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)wereaparticularlypotentstimulatorofsystemicantitumorimmunity.Extendingthisfinding,severalearly-stageclinicaltrialswereconductedinthelate1990swithautologousGM-CSF-secretingtumorvaccineswhichshowedpromisingresultsinpatientswithprostateandrenalcellcarcinomaandmelanoma.Basedontheseresultsandtheinherenttechnicalandregulatorydifficultiesassociatedwithautologousvaccines,theJohnsHopkinsgroupbeganpursuingdevelopmentofanirradiated,allogeneicGM-CSF-transducedcellularvaccineagainstpancreaticcancer.PancreaticcancerwaschosenasthetargetbasedonbothclinicalneedandtheassociationoftheinvestigatorswiththeJohnsHopkinsGISPORE.
Developmentoftheallogeneicvaccinerequiredestablishingnewmethodsforgenerationofin vitrocelllinesfromprimarytumorsaswellasanimalmodelsandin vitroassays.FortheinitialPhaseItrialbegunin1997,thenewallogeneiclinesweregeneticallymodifiedtoexpressGM-CSFandclinicalgradevaccinewasproducedbyacontractmanufacturerusingfundsprovidedbyaprivatedonor.ThevaccinedevelopmentandclinicaltrialcostswerefundedbyacombinationofNCIR01,SPORE,andtrainingawards.APhaseIItrialwasinitiatedin1999undertheHopkinsGISPOREusingvaccinepreparedbytheNCIRapidAccesstoInterventionDevelopment(RAID)program.
Asdevelopmentprogressed,theJohnsHopkinsgroupappliedforandreceivedU.S.patentscoveringabroadmethodfortreatingpancreaticcancerusingallogeneicpancreatictumorcelllinesmodifiedtoproduceacytokinethatstimulatesanantitumorresponseaswellasspecificcelllinesandcelllineproductionmethods.Thesepatentsandtheunderlyingvaccinetechnologywerelicensedin2001toCellGenesys,whoprovidedadditionalfundingfortheinitialPhaseIItrial.CellGenesysthensupportedasecondPhaseIItrialinmetastaticpatientscomparingthevaccinealonewithvaccineplusimmunemodulatingdosesofcyclophosphamidetodepleteregulatoryTcells.TwoadditionalPhaseIItrialsarealsonowunderway—oneexaminingthevalueofboostervaccinationsandthesecondtestingthevaccineincombinationwithcyclophosphamideandcetuximab.
Basedonthesuccessofthiscell-basedvaccinedevelopmentprogram,in2001JohnsHopkinsbegantodevelopaGMPvaccinemanufacturingcapabilityasaCancerCenterP30-supportedcoreresource.Thisfacilitybecamefullyoperationalin2004andhasfacilitatedrefinementofseveralothervaccinedevelopmentconceptsandexpandedthepoolofJohnsHopkinsinvestigatorsdevelopingvaccinesforclinicaltrials.
Relationship to TRWG Pathway
DevelopmentofthevaccinefollowedtheimmuneresponsemodifierpathwaythroughmultipleiterationsstartingwithautologousvaccinestestedinPhaseItrialsforseveraldifferentcancersbeforefocusingonanallogeneicvaccineforpancreaticcancerastheprimarydevelopmentalfocus.
Bottlenecks
Theprimarybottleneckidentifiedbytheinvestigatorwasmanufacturing.FundsfromprivatesourceswereneededforinitialPhaseImanufacturingandwithoutinvolvementoftheNCIRAIDprogramthevaccinemayneverhaveproceededtoPhaseIItrials.ThisexperienceledtheCancerCenteratJohnsHopkinstodevelopaGMPvaccinemanufacturingfacilityasacoreresource.
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Key Observations
1. Intheareaofimmuneresponsemodifiers,itcanbedifficulttoobtainR01fundingfor“credentialing”adiscoveryforentryintotheTRWGdevelopmentalpathway.Becausetheapproachescanbequitenovel,researchersoftenmustusetrainingawards,SPOREfunds,orotherfundingsourcestoconductthenecessarystudies.
2. Completingthelaterstagesofdevelopment(e.g.,manufacturingandearly-stagetrials)requiredtheinvestigatortoassemblefundsfromseveraldifferentgovernmentprogramsaswellasprivatesources.
3. MultiplePhaseItrialsofinitialvaccineconceptswerenecessarytoprovideproofofprincipleandidentifydevelopmentalbottleneckstobeovercome(i.e.,promisingresultswithautologousvaccinesleadtodevelopmentofamorepracticalallogeneicversion).
4. Successfulhandofftoindustryforfurtherdevelopmentwasfacilitatedbyastrongintellectualpropertyposition,RAIDfundingofvaccineproduction,andSPOREfundingofaninitialPhaseIItrial.
5. Anacademicmedicalcenter’sinvestmentinGMPmanufacturingcapabilitiescanleadtosubstantialexpansionofrelatedtranslationalresearchattheinstitution.
Sources
• InterviewwithDr.ElizabethJaffee,JohnsHopkinsUniversity(February1,2006)
Literature
• DranoffG,JaffeeE,LazenbyA,GolumbekP,LevitskyH,BroseK,JacksonV,HamadaH,PardollD,MulliganRC.Vaccinationwithirradiatedtumorcellsengineeredtosecretemurinegranulocyte-macrophagecolony-stimulatingfactorstimulatespotent,specific,andlong-lastinganti-tumorimmunity.ProcNatlAcadSci.1993;90(8):3539-43.
• JaffeeEM,SchutteM,GossettJ,MorsbergerLA,AdlerAJ,ThomasM,GretenTF,HrubanRH,YeoCJ,GriffinCA.Developmentandcharacterizationofacytokine-secretingpancreaticadenocarcinomavaccinefromprimarytumorsforuseinclinicaltrials.CancerJSciAm.1998;4(3):194-203.
• JaffeeEM,AbramsR,CameronJ,DonehowerR,DuerrM,GossettJ,GretenTF,GrochowL,HrubanR,KernS,LillemoeKD,O’ReillyS,PardollD,PittHA,SauterP,WeberC,YeoC.AphaseIclinicaltrialoflethallyirradiatedallogeneicpancreatictumorcellstransfectedwiththeGM-CSFgeneforthetreatmentofpancreaticadenocarcinoma.HumGeneTher.1998;9(13):1951-71.
• JaffeeEM,HrubanRH,BiedrzyckiB,LaheruD,SchepersK,SauterPR,GoemannM,ColemanJ,GrochowL,DonehowerRC,LillemoeKD,O’ReillyS,AbramsRA,PardollDM,CameronJL,YeoCJ.Novelallogeneicgranulocyte-macrophagecolony-stimulatingfactor-secretingtumorvaccineforpancreaticcancer:aphaseItrialofsafetyandimmuneactivation.JClinOncol.2001;19(1):145-56.
Patent Search
• Jaffeeetal.Methodoftreatingcancerwithatumorcelllinehavingmodifiedcytokine(#6,033,6�4).FiledDecember26,1996;receivedMarch7,2000.
• Jaffeeetal.Purifiedpancreatictumorcelllinesandrelatedcompositionsandmethod(#5,985,290).FiledMarch18,1998;receivedNovember16,1999.Subsequentpatentsinclude#6,193,9�0and#6,350,445.
• Jaffeeetal.Growthmediumforprimarypancreatictumorcellculture(#6,087,174).FiledMarch18,1998;receivedJuly11,2000.
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Radiofrequency Ablation
Summary
Radiofrequency(RF)ablationuseselectromagneticenergytoheatanddestroytissue.Thetechniquewasinitiallydevelopedforuseincardiology,primarilyasatreatmentforarrhythmias,andtheFDAapprovedcardiacRFablationdevicesin1994.Inearly1995,ItalianclinicianspresentedaseriesofcasereportsonusingRFablationtotreatlivercancerandresearchersattheUniversityofCaliforniaDavisreportedresultsfromRFablationofprostatetissueindogs.Duringtheperiod1995-1997,investigatorsatmultipleinstitutionsintheUnitedStatesandEuropereportedanumberofanimal,phantom,andexploratoryhumanstudiesexaminingRFablationforuseincancerintervention.Themajorityofthisworkwassupportedbyadhoclocalfundingratherthanbyatraditionalgrantmechanism.
ThefirstformalPhaseItrial,performedbyresearchersatCaseWesternReserveUniversity,wasreportedin1998.EvenafterthisfirstPhaseItrial,multipleresearchgroupsworldwidecontinuedtoexamineRFablationinbothphantomandanimalstudiesinordertorefineprocedures.AlthoughsomeofthesestudieswereNCIfundedthroughR01andSBIRawardsaswellasoneSPOREproject,mostofthepreclinicalworkwasfundedbyindustry.MultipleNCI-fundedPhaseIItrials,primarilyinpatientswithliverorrenalcancerwhowerenotcandidatesforsurgicalresection,werecarriedoutbeginninginthelate1990s.APhaseIIItrialcomparingsurgerydirectlywithRFablationinrenalcarcinomawasinitiatedin2005inFranceandisstillaccruingpatients.
Relationship to TRWG Pathway
AsRFablationdeviceswereoriginallydevelopedandFDAapprovedforanononcologypurpose,translationintooncologyproceededwithclinicalstudiesbeingconductedinparallelwithstudiesonphantomsandanimalsratherthaninsequentialfashionasdescribedbythepathway.
Bottlenecks
Therewerenosignificantbottlenecksencountered.
Key Observations
1. Interventionaldevicedevelopmentoftenproceedsthoughalearn-by-doingapproachwherebyclinicaltrial-and-errorisusedtorefinethetechniqueratherthanproceedingthroughastructuredpreclinicalvalidationprocessleadingtodefinitiveclinicaltrials.
2. Becauseinterventionaldevicedevelopmentisstronglydrivenbyindustry,particularlysmallcompanies,devicesareoftenmovedforwardintoclinicaltrialsandclinicalpracticewithoutsubstantialoptimization.Onceadeviceisapproved,itisdifficulttoobtaineitherindustryorgovernmentfundingforoptimizingitsuse(e.g.,optimizingthetime,size,andprecisionofRFablationtherapy).
3. Developmentofastrongerpreclinicaltestinginfrastructureforinterventionaldevicesmaybebeneficialinthelongrunasmoreeffortwouldbepaidtooptimization(andtheutilityofthetechniquerelativetocompetingapproaches)beforethedeviceisbroughtintotheclinic.
4. Developmentofastrongerearlyclinicaltestinginfrastructureforinterventionaldevices(comparabletotheCooperativeGroups)andmechanismsformulticenterdatabasereportingwillbeimportanttoensureefficienttranslationofpreclinicalstudiesandrobustevaluationofsafetyandefficacy.
Sources
• FDACenterforDevicesandRadiologicalHealth,Devices@FDAdatabase
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 143
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• InterviewwithDr.NahumGoldberg,BethIsraelDeaconessMedicalCenter(February7,2006)
Literature
• ManolisAS,WangPJ,EstesNAIII.Radiofrequencycatheterablationforcardiactachyarrhythmias.AnnInternMed.1994;121(6):452-61.
• BuscariniL,RossiS,FornariF,DiStasiM,BuscariniE.Laparoscopicablationofliveradenomabyradiofrequencyelectrocauthery.GastrointestEndosc.1995;41(1):68-70.
• McGahanJP,GriffeySM,BudenzRW,BrockJM.Percutaneousultrasound-guidedradiofrequencyelectrocauteryablationofprostatetissueindogs.AcadRadiol.1995;2(1):61-5.
• DjavanB,SusaniM,ShariatS,ZlottaAR,SilvermanDE,SchulmanCC,MarbergerM.Transperinealradiofrequencyinterstitialtumorablation(RITA)oftheprostate.TechUrol.1998;4(2):103-9.
• LewinJS,ConnellCF,DuerkJL,ChungYC,ClampittME,SpisakJ,GazelleGS,HaagaJR.InteractiveMRI-guidedradiofrequencyinterstitialthermalablationofabdominaltumors:clinicaltrialforevaluationofsafetyandfeasibility.JMagnResonImaging.1998;8(1):40-7.
• AhmedM,LiuZ,AfzalKS,WeeksD,LoboSM,KruskalJB,LenkinskiRE,GoldbergSN.Radiofrequencyablation:effectofsurroundingtissuecompositiononcoagulationnecrosisinacaninetumormodel.Radiology.2004;230(3):761-67.
• GoldbergSN,BonnJ,DoddG,DupuyD,GeschwindJ,HicksM,HumeKM,LeeFT,LewisCA,LencioniRA,OmaryRA,RundbackJH,SilvermanS,DorfmanGS,SocietyofInterventionalRadiologyInterventionalOncologyTaskForce.Interventionaloncologyresearchvisionstatementandcriticalassessmentofthestateofresearchaffairs.JVascIntervRadiol.2005;16:1287-94.
144 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
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Three-Dimensional Conformal Radiation Therapy for Prostate Cancer
Summary
Radiationtherapyrequirescarefulplanningtodirecttheradiantenergytotumortissuewhilelargelysparingsurroundinghealthytissue.Inthe19�0s,thearrivalofCTscantechnologygaveclinicians,forthefirsttime,detailedanatomicalinformationaboutthelocationofatumoranditssurroundingtissue.Three-dimensional(3-D)visualizationwasperformedmanuallybyusingmultiple2-DCTimagestodeterminetheoptimalgeometryforradiationdelivery.Althoughcomputerswereappliedtoradiotherapytreatmentplanningasearlyas1955,thehugegrowthincomputerpowerthroughthe1970sand1980smadepossiblethedevelopmentofalgorithmsforaccuratethree-dimensionalvisualizationofatumorandcreationofmoreoptimalradiationtreatmentplans,offeringthepotentialfordecreasederrorratesandincreaseddosesofradiationtocanceroustissue.
Duringthelate1970sandearly1980s,developmentofcomputer-assistedthree-dimensionaltumorvisualizationandradiationtherapytreatmentplanningwasundertakensimultaneouslybymanygroupsofinvestigators.Thefirst3-DplanningdevelopmentswerereportedbyMcShanetal.atRhodeIslandHospital(laterrelocatedtotheUniversityofMichigan)andGoitein,etal.,atMassachusettsInstituteofTechnologyandMassachusettsGeneralHospital(MGH).By1987,manygroupsweredeveloping3-Dplanningsystems.
Theearliestuseof3-DsystemsoccurredintheparticletherapyeffortsatMGHandtheUniversityofCaliforniaatBerkeley,whileroutineclinicaluseofafullyintegrated3-Dplanningsystemstartedin1986attheUniversityofMichigan.Duringthemidandlate1980s,NCIusedtheN01contractmechanismtofunddevelopmentandcomparisonstudiesofbothphotonandelectron3-Dplanningatanumberofinstitutions.Thesestudiesfurtherdocumentedthepotentialvalueof3-Dplanningbytestingthemethodologyinparallelatmultipleinstitutionsinordertodemonstratereproducibilitywhenusedbydifferentmachinesandoperators.
ThefirstPhaseItrialofthethree-dimensionaltumorlocalizationandtreatmentplanningsystembeganin198�attheUniversityofMichiganwithdoseescalationtrialsinprostateandlivercancer,followedbyalargerdoseescalationprostatecancertrialin1991atMemorialSloan-KetteringCancerCenterusingNCIP01funding.Duringthelate1980sandearly1990s,investigatorsatseveralinstitutions,someusingN01orP01funding,continuedtomakeimprovementsinthealgorithmsandcapabilitiesofthesystemsandtoextendtheiruseinclinicalsettings.AnumberofPhaseI/IItrialswereperformedinsingleinstitutionsettingsthroughthelate1990s,somewithNCIfunding.
Relationship to TRWG Pathway
Developmentofthree-dimensionalconformalradiationtherapyfollowedtheinterventionaldevicepathwayclosely.However,becauseofthenatureofthetechnology,itwaspossibletointroduceuseofthree-dimensionalconformalradiationtherapyintoclinicalpracticeinadvanceofcontrolledPhaseIandIItestingofitsutilityinguidingenhancedtherapyregimenssuchasdoseescalation.
Bottlenecks
Nosignificantearlytranslationalbottleneckswerereported.
Key Observations
1. Developmentrequiredthatmultipleinstitutionsbeinvolvedinboththevalidationphaseandinclinicaltrialstoensurethatoperator/machinerycharacteristicsdidnotbiastheresults.
2. AcombinationofNCIcontractandgrantfundingwasusedtosupportboththevalidationandearlyclinicaltrialphases.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 145
Report of the NCAB Translational Research Working Group—Appendix E
Sources
• InterviewwithDr.TedLawrence,UniversityofMichigan(December29,2005)
Literature
• DLMcShan,ASilverman,DLanza,LEReinstein,ASGlicksman:Acomputerizedthree-dimensionaltreatmentplanningsystemutilizinginteractivecolorgraphics.BritJRad.1979;52:478-81.
• GoiteinM,AbramsM,RowellD,PollariH,WilesJ.Multi-dimensionaltreatmentplanning:II:Beam’seye-view,backprojection,andprojectionthroughCTsections.IntJRadiatOncolBiolPhys.1983;9(6):780-97.
• GWSherouse,CEMosher,KNovine,JRosenman,EChaney:Virtualsimulation:conceptandimplementation.In:BruinvisIAD,vanderGiessenFH,vanKleffensHJ,WittkamperFW,eds.TheUseofComputersinRadiationTherapy.North-Holland:Elsevier;1987,pp.423-36.
• MohanR,BarestG,BrewsterLJ,ChuiCS,KutcherGJ,LaughlinJS,FuksZ.Acomprehensivethree-dimensionalradiationtreatmentplanningsystem.IntJRadiatOncolBiolPhys.1988;15(2):481-95.
• McShanDL,FraassBA,LichterAS.Fullintegrationofthebeam’seyeviewconceptintocomputerizedtreatmentplanning.IntJRadiatOncolBiolPhys.1990;18(6):1485-94.
• TSLawrence,RJTesser,RKTenHaken:Anapplicationofdosevolumehistogramstotreatmentofintrahepaticmalignancieswithradiationtherapy.IntJRadOncolBiolPhys.1990;19:1041-7.
• SimpsonJR,PurdyJA,ManolisJM,PilepichMV,BurmanC,FormanJ,FuksZ,ChengE,ChuJ,MatthewsJ,etal.Three-dimensionaltreatmentplanningconsiderationsforprostatecancer.IntJRadiatOncolBiolPhys.1991;21(1):243-52.
• SandlerHM,Perez-TamayoC,TenHakenRK,LichterAS.DoseescalationforstageC(T3)prostatecancer:Minimalrectaltoxicityobservedusingconformaltherapy.RadiotherOncol.1992;23:53-4.
• LeibelSA,ZelefskyMJ,KutcherGJ,BurmanCM,KelsonS,FuksZ.Three-dimensionalconformalradiationtherapyinlocalizedcarcinomaoftheprostate:interimreportofaphase1dose-escalationstudy.JUrol.1994;152(5Pt2):1792-8.
146 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix E
Exercise, Diet, and Breast Cancer
Summary
Intheearly1990s,severalobservationalstudieswerereportedindicatingthatexcessweightandobesityareassociatedwithpoorerprognosisandsurvivalforbreastcancerpatients.Additionally,aspartofanNCI-fundedcohortstudythathasfollowed1,185breastcancercasesfor10years,theMcTiernangroupattheFredHutchinsonCancerResearchCenterinterviewedstudyparticipantstodeterminephysicalactivitybothpre-andpostdiagnosis.Inpreliminaryanalyses,theynotedthatwomenwhowerephysicallyactivebothpre-andpostdiagnosishadlowerrecurrenceofbreastcancer,whichsuggestedthatincreasingactivitycouldpotentiallyimproveprognosis.
However,becauseweight,diet,andphysicalactivityarehighlycorrelated,itwasdifficulttoassesstheirindependentcontributionstobreastcancerprognosisfromsuchobservationalstudies.Therefore,theMcTiernangroupconductedapilotdiet-exerciseinterventionstudy(fundedbyaClinicalResearchCenterawardfromtheNationalCenterforResearchResources)innineoverweight,sedentarybreastcancerpatientstotestthefeasibilityofsuchatrial.Theresultsreportedin1998indicatedthatrecruitmentsuccessandcompliancewereveryhighandthatsignificantreductionsinweight,bodyfat,bloodpressure,andpulsewereachieved.
Basedonthefeasibilitydemonstratedbythispilotstudy,theMcTiernangroupobtainedanNCIR01grantin1997whichfundedrandomizedcontrolledstudiesexaminingtheeffectofa1-year,moderateintensityexerciseprogramonhormonelevels(asapotentialsurrogateforoutcome)ofapproximately170sedentary,overweightpostmenopausalwomen.Resultsshoweddecreasesinserumestrogen,testosterone,andinsulin,whichmayexplaintheassociationofexercisewithreducedcancerrecurrence.Largeobservationalstudiesontherelationshipofexercise,diet,andsexhormoneorinsulinlevelsonbreastcancerriskcontinuetobereported,butnofurtherlarge,controlledinterventionalstudieshavebeenpublished.
Relationship to TRWG Pathway
Assessingeffectivenessofexerciseanddietonbreastcancerriskfollowedthelifestyleinterventionpathwayclosely.
Bottlenecks
TheprimarybottleneckreportedwasaperceivedlowpriorityforlifestyleinterventionresearchatNCI.OtherInstitutessuchastheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesandtheNationalHeart,Lung,andBloodInstitutewerecharacterizedasbeingmoreaccustomedtofundingthistypeofresearch.
Key Observations
1. Small,carefullycontrolledpilotstudiesoflifestyleinterventionsarecriticaltoestablishfeasibilityofpatientrecruitmentandcompliance.
2. ItisdifficulttofundpilotlifestyleinterventionstudieswithtraditionalNCIgrants.ItisoftenusefultouseCancerCenterorotherinfrastructureresourcestofundsuchpilotstudiesandbuildthepremiseformoredefinitivetrials.
Sources
• InterviewwithDr.AnneMcTiernan(February7,2006)
Literature
• McTiernanA,UlrichC,KumaiC,BeanD,SchwartzR,MahlochJ,HastingsR,GralowJ,PotterJD.Anthropometricandhormoneeffectsofaneight-weekexercise-dietinterventioninbreastcancerpatients:resultsofapilotstudy.CancerEpidemiolBiomarkersPrev.1998;7(6):477-81.
Transforming Translation—Harnessing Discovery for Patient and Public Benefit 147
Report of the NCAB Translational Research Working Group—Appendix E
• ChlebowskiRT,AielloE,McTiernanA.Weightlossinbreastcancerpatientmanagement.JClinOncol.2002;20(4):1128-43.
• McTiernanA,TworogerSS,RajanKB,YasuiY,SorensonB,UlrichCM,ChubakJ,StanczykFZ,BowenD,IrwinML,RudolphRE,PotterJD,SchwartzRS.Effectofexerciseonserumandrogensinpostmenopausalwomen:a12-monthrandomizedclinicaltrial.CancerEpidemiolBiomarkersPrev.2004;13(7):1099-105.
• McTiernanA,TworogerSS,UlrichCM,YasuiY,IrwinML,RajanKB,SorensenB,RudolphRE,BowenD,StanczykFZ,PotterJD,SchwartzRS.Effectofexerciseonserumestrogensinpostmenopausalwomen:a12-monthrandomizedclinicaltrial.CancerRes.2004;64(8):2923-8.
148 Transforming Translation—Harnessing Discovery for Patient and Public Benefit
Report of the NCAB Translational Research Working Group—Appendix E
Smoking Cessation and Lung Cancer
Summary
Becauseofthewell-documentedcausaleffectofsmokingonlungcancerandpreviousstudiesofsmokingcessationinterventioninothertypesofcancer,arandomizedtrialofasmokingcessationinterventionforearly-stagelungcancerpatientswasdesignedbyDrs.Gritz(M.D.AndersonCancerCenter)andAlbain(LoyolaUniversity)intheCancerControlResearchCommitteeoftheSouthwestOncologyGroup(SWOG).ThetrialwasimplementedinSWOGandotheraffiliatedcooperativeoncologygroups.Becausepreviousworkhadidentifiedinterventionsthatwouldfacilitatesmokingcessation,apilotstudywasnotconductedinadvanceofstartingthisPhaseIIItrialin2002.However,membersoftheSWOGLungCommitteeweresurveyedregardingtheirsupportofthistrialpriortoitsinceptionandtheresponsewasextremelypositive.Smokingstatusdatawerealsosampledfromapriorclinicaltrialinlungcancerpatientstoestimatesmokingprevalenceintherelevantpopulation.Theinvestigatorsobtainedsupportfromapharmaceuticalcompanytocarryoutthisstudy.
After2yearsofimplementation,activetrainingattwoSWOGmeetings/year,andsignificantoutreachtoothercooperativegroups,thetrialwasclosedduetolackofaccrual.Accrualbarriersincluded(a)difficultyinaccessingpatients,asstageIandIIlungcancerpatientsaregenerallytreatedbysurgeons,notbymedicaloncologists;(b)lackofincentivesforinvestigatorstoparticipate,duetolow-levelreimbursementperpatient;and(c)perceiveddifficultiesinconductingtheinterventionandfollow-up,asnursesandSWOGpatientcoordinatorsaremoreaccustomedtomedicalinterventionswhichrequirelesspatient-completedassessment.
Relationship to TRWG Pathway
Developmentofthesmokingcessationinterventiondidnotfollowthepathwayinthatapilotstudytoassessfeasibilitywasnotconducted.
Bottlenecks
Theprimarybottleneckwasextremedifficultyinaccruingpatientstothisinterventiontrial.SignificantdelaysinreceivingNCIapprovaltoconductthetrialandtheneedtoobtainexternalfundingwerealsobarriers.
Key Observations
1. Pilotstudiestoassessfeasibilityofpatientrecruitmentandcomplianceaswellasotherlogisticalaspectsofalargedefinitivetrialarecriticalelementsinsuccessfullifestyleinterventiondevelopment.
2. Lifestyleinterventionstudiesincancersurvivorsarenotahighpriorityforoncologycooperativegroupsandrequireintensiveeffortstodevelop,fund,accruepatients,andsuccessfullycomplete.Inthiscase,thelattertwoobjectiveswerenotachieved.
Sources
• InterviewwithDr.EllenGritz,TheUniversityofTexasM.D.AndersonCancerCenter(February7,2006).
Literature
• GritzER,NisenbaumR,ElashoffRE,HolmesEC.SmokingbehaviorfollowingdiagnosisinpatientswithstageInon-smallcelllungcancer.CancerCausesControl.1991;2(2):105-12.
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Report of the NCAB Translational Research Working Group—Appendix E
• GritzER,CarrCR,RapkinD,AbemayorEA,ChangLJ,WongWK,BelinTR,CalcaterraT,RobbinsKT,ChonkichG,BeumerJ,WardPH.Predictorsoflong-termsmokingcessationinheadandneckcancerpatients.CancerEpidemiolBiomarkersPrev.1993;2(3):261-70.
• GritzER,SchachererC,KoehlyL,NielsenIR,AbemayorE.Smokingwithdrawalandrelapseinheadandneckcancerpatients.HeadNeck.1999;21(5):420-7.
• GritzER,DreslerC,SarnaL.Smoking,themissingdruginteractioninclinicaltrials:ignoringtheobvious.CancerEpidemiolBiomarkersPrev.2005;14(10):2287-93(andreferencescitedtherein).
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Report of the NCAB Translational Research Working Group—Appendix F
Appendix F: TRWG Meeting Dates
2005
November15-21TRWGConferenceCalls
December4-5TRWGFace-to-FaceMeetingBaltimore,MD
December7PresentationtoNationalCancerAdvisoryBoardBethesda,MD
2006
February23-24TRWGFirstPublicRoundtablePhoenix,AZ
March23-24TRWGFace-to-FaceMeetingBethesda,MD
April24TRWGIndustry,Foundation,SocietyRoundtablePhiladelphia,PA
May30-31TRWGFace-to-FaceMeetingHouston,TX
June14InterimReporttoNationalCancerAdvisoryBoardBethesda,MD
June30InterimReporttoNCIBoardofScientificAdvisorsBethesda,MD
August16-17TRWGFace-to-FaceMeetingChicago,IL
September14-15TRWGFace-to-FaceMeetingHerndon,VA
October16-17TRWGSecondPublicRoundtableAtlanta,GA
November27-28TRWGFace-to-FaceMeetingBethesda,MD
2007
January17-18TRWGFace-to-FaceMeetingMillbrae,CA